Mercaptopurine
Drug Related WarningMercaptopurine
The drug shouldn't be used until acute lymphatic leukaemia has been conclusively diagnosed and the patient's doctor is experienced in determining how well the patient responds to chemotherapy.
Medicine Type :
Allopathy
Allopathy
Prescription Type:
Prescription Required
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Schedule H
Pharmacological Class:
Antimetabolites, Immunomodulatory agents, Therapy Class:
Antineoplastic agent, Approved Countries
India, the United States, Canada, the United Kingdom, Germany, Australia, Japan, France, Italy, and Spain
Mercaptopurine is an antineoplastic agent belonging to the pharmacological class of Antimetabolites.
Mercaptopurine is FDA-approved for treating acute lymphoblastic leukaemia (ALL).
Mercaptopurine's bioavailability varies from 5% to 37%, indicating inadequate absorption from the gastrointestinal system. It crosses the blood-brain barrier, binds to about 19% of plasma proteins, is extensively metabolized in the liver and is mainly eliminated through urine with approximately 46%.
The most common side effects of Mercaptopurine include nausea, vomiting, diarrhea, rash, and loss of appetite.
Mercaptopurine is available as tablets and oral suspensions.
The molecule is available in India, the United States, Canada, the United Kingdom, Germany, Australia, Japan and Brazil.
Mercaptopurine is an antineoplastic agent belonging to the pharmacological class of Antimetabolites.
An analogue of purine nucleoside, Mercaptopurine is a prodrug that metabolizes to thioguanine nucleotide (TGN). TGN is integrated into the DNA and RNA and prevents nucleic acid production, ultimately resulting in cell death. It also inhibits the de novo synthesis and interconversions of purines.
Mercaptopurine reaches peak plasma time approximately 2 hours after administration.
Mercaptopurine begins to take effect within 2 hours of administration.
Mercaptopurine is available as tablets and oral suspensions.
- Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.
- Oral suspension: Shake well before each use. Measure the dose carefully with the provided device and take it as directed.
The physician recommends taking this medication orally once daily, with or without meals.
- Acute Lymphoblastic Leukemia
- Crohn's Disease (Off-label)
Acute Lymphoblastic Leukemia: In the treatment of Acute Lymphoblastic Leukemia (ALL), Mercaptopurine proves effective, particularly during the maintenance phase. It disrupts DNA and RNA synthesis in rapidly dividing leukemic cells, inducing their death. The continuous use of Mercaptopurine in the maintenance phase sustains achieved remission, reducing the risk of relapse, and improving overall survival rates.
Mercaptopurine is indicated for the maintenance of a combined chemotherapy regimen in the treatment of adult and pediatric patients with acute lymphoblastic leukaemia (ALL).
Orally: Administer Mercaptopurine tablets orally with or without food. Swallow the tablets whole with a full glass of water. Shake the oral suspension well before each use. Measure the prescribed dose accurately using the provided device. Take the suspension directly from the measuring device or mix it with a small amount of food or liquid. Do not take extra doses if a dosage is missed; take it as soon as you recall. As directed by the healthcare provider, adhere to the recommended dose standards.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
- Tablet: 50mg
- Oral suspension: 20mg/mL
Mercaptopurine is available as tablets and oral suspensions.
Dose Adjustment in Adult Patients:
Acute Lymphatic Leukemia
Induction: 2.5 mg/kg PO daily; for an average adult, this is typically 100–200 mg PO qDay (other drugs preferred)
After four weeks, it may increase by 5 mg/kg/day.
Maintenance: 1.5- to 2.5 mg/kg PO daily
Lower dosage by 75% if allopurinol is being administered concurrently.
Lower the dosage when there is renal impairment.
Crohn's Disease (Off-label)
1-1.5 mg/kg PO qHS
While on Mercaptopurine, managing side effects is possible through dietary adjustments. Patients should consume low-fat proteins like lean meats, fish, and poultry and a balanced diet full of fruits and vegetables high in vital nutrients. Drinking lots of water regularly is crucial to staying hydrated, especially when some cancer treatments can cause dehydration. People should also maintain proper hygiene, wash their hands often, and keep their distance from individuals who are ill. Quitting smoking is also recommended.
The dietary restriction should be individualized as per patient requirements.
- History of severe hypersensitivity to Mercaptopurine or any of the excipients.
- Pregnancy and lactation.
- Myelosuppression: Regularly monitor complete blood count (CBC) and adjust Mercaptopurine dosage in cases of excessive myelosuppression. Consider screening for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency, especially in patients experiencing severe or recurrent myelosuppression. Homozygous or compound heterozygous TPMT or NUDT15 deficient patients may require a dose reduction.
- Hepatotoxicity: Monitor transaminases, alkaline phosphatase, and bilirubin levels. Suspend Mercaptopurine immediately if hepatotoxicity is detected.
- Immunosuppression: Expect a reduced response to all vaccines, and there is an increased risk of infection with live virus vaccines. Consult immunization guidelines for immunocompromised patients.
- Treatment-Related Malignancies: Cases of aggressive and fatal hepatosplenic T-cell lymphoma have been reported.
- Macrophage Activation Syndrome: Be vigilant for symptoms and treat macrophage activation syndrome promptly. Discontinue Mercaptopurine in such cases
- Embryo-Fetal Toxicity: Mercaptopurine can cause fetal harm. Advise patients of reproductive potential about the potential risk to a fetus and recommend the use of effective contraception.
Alcohol Warning
It is unsafe to consume Mercaptopurine with alcohol.
Breast Feeding Warning
It is unsafe to use Mercaptopurine during breastfeeding.
Pregnancy Warning
It is not recommended for use during pregnancy.
Food Warning
Consume a low-fat protein diet and avoid smoking.
The adverse reactions related to Mercaptopurine can be categorized as:
- Common Adverse Effects: Elevated LFTs
- Less Common Adverse Effects: Nausea, vomiting, stomatitis, thrombocytopenia, rash, diarrhoea, dizziness, alopecia, and leukopenia.
- Rare Adverse Effects: Severe bone marrow suppression, increasing the risk of infection, anaemia, and bleeding.
Reports on Post-Marketing
Photosensitivity
Low blood sugar
Portal hypertension
The syndrome of macrophage activation
Urticaria
Raised bilirubin levels
Bone marrow toxicity
Hyperuricosuria or hyperuricemia
Skin irritations and hyperpigmentation
Alopecia
Fever rarely
The clinically relevant drug interactions of Mercaptopurine are briefly summarized here.
Drug-Drug Interactions
Reduces the anticoagulant's physiological activity (e.g. warfarin, acenocoumarol). It may decrease the body's reaction to vaccinations. Increased side effects when using xanthine oxidase inhibitors (such as febuxostat, allopurinol, oxipurinol, and thiopurinol). Increased myelosuppression in combination with co-trimoxazole, ribavirin, and other myelosuppressive drugs; examples of these are mesalazine, olsalazine, and sulfasalazine. Increased risk of lymphoproliferative diseases linked to the Epstein-Barr virus while using numerous immunosuppressive medications.
Food Interaction
Reduced bioavailability while consuming dairy, milk, or food.
The common side effects of Mercaptopurine include:
Nausea
Vomiting
Rash
Low platelet counts in the blood
Decreased number of neutrophils, or white blood cells
Stomach ulcer
Mouth inflammation
Anaemia, or reduced red blood cell count
Increased bilirubin in the blood
Increased transaminase level in blood
Diarrhea
Loss of appetite
Pregnancy
Pregnancy Category D (FDA): Use in cases where no safer medication is available, and life is in danger. Positive evidence of prenatal risk in humans.
Pregnant women who receive Mercaptopurine have a higher chance of miscarriage and stillbirth; inform them of the possible danger to the fetus. Therapy can affect the developing foetus.
Before starting treatment, find out whether any females who are capable of bearing children are pregnant.
Possibility of reproduction
Advise women who are capable of having children to utilize reliable contraception both during their therapy and for six months following their final dosage.
Men: Males who have female partners who may get pregnant should be advised to utilize effective contraception during PURIXAN therapy and for three months following the final dosage, according to genotoxicity data.
Infertility
Males and females: Research on animals has shown that drugs can reduce the fertility of both sexes; however, the long-term consequences of these drugs, particularly their reversibility, have not been examined.
Animal data
The medication showed teratogenic and embryo-lethal in several animal species, including rats, mice, rabbits, and hamsters, at dosages lower than those advised for humans.
- Nursing Mothers
Due to the possibility of severe adverse reactions in breastfed children, it is advised that mothers not breastfeed during treatment and for one week following the last dosage. There is no data on the presence of Mercaptopurine or its metabolites in human milk, their effects on breastfed children, or their milk production.
- Pediatric Use
Pediatric patients have demonstrated the safety and efficacy of Mercaptopurine. Empirical research and published literature provide evidence of using Mercaptopurine in paediatrics. Children with ALL who are given Mercaptopurine have been known to have symptomatic hypoglycemia. Patients under six or those with low body mass index were the subjects of reported events in paediatrics.
Dose Adjustment
Acute Lymphatic Leukemia
Starting dose: 1.25 to 2.5 mg/kg (50-75 mg/m²) PO daily
Maintenance dose: 1.5 to 2.5 mg/kg PO daily in combination with methotrexate
Lower dosage by 75% if allopurinol is being administered concurrently.
Lower the dosage when there is renal impairment.
- Geriatric Use
There were insufficient patients 65 years of age and older in clinical trials of Mercaptopurine to assess if their responses differed from those of younger subjects. Elderly and younger individuals do not respond differently, according to other documented clinical experiences. Given the increased incidence of reduced hepatic, renal, or cardiac function, concurrent illness, or other medication therapy, dosage selection for an elderly patient should generally be conservative and begin at the low end of the dosing range.
Dose Adjustment in Kidney Impairment Patients:
For patients with renal impairment (CLcr less than 50 mL/min), start with the lowest recommended dosage for Mercaptopurine Tablets or extend the dosing interval to every 36 to 48 hours. Adjust the dosage to prevent unwanted side effects and maintain the absolute neutrophil count (ANC) at a desired level.
Dose Adjustment in Hepatic Impairment Patients:
For individuals with hepatic impairment, start with the lowest suggested dosage of Mercaptopurine. Adjust the dosage to prevent unwanted side effects and keep the absolute neutrophil count (ANC) at a desired level.
The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Mercaptopurine.
Signs and Symptoms
Immediate: Anorexia, nausea, vomiting, and diarrhoea);
Delayed: Myelosuppression, liver dysfunction, and gastroenteritis.
Management
No specific antidote exists for Mercaptopurine overdose. In the event of an overdose, promptly initiate appropriate supportive measures. Dialysis is unlikely to effectively clear the drug due to rapid intracellular incorporation into long-persisting active metabolites. Suspend Mercaptopurine immediately in the presence of severe or life-threatening adverse reactions. If accidental overdosage is detected promptly, inducing emesis may be considered.
Pharmacodynamics:
Mercaptopurine is one of many purine analogues that have been shown to be effective against human leukaemias and interfere with nucleic acid production. It is a purine-based counterpart of hypoxanthine and adenine. It is unknown which one or more of the metabolic activities of Mercaptopurine and its metabolites specifically cause cell death, either directly or indirectly.
Pharmacokinetics:
- Absorption: Food consumption may decrease the bioavailability of Mercaptopurine due to its inconsistent and partial absorption in the gastrointestinal system. Peak plasma concentration is reached in less than two hours, and the bioavailability varies from 5% to 37%.
- Distribution: Approximately 19% of Mercaptopurine binds to plasma proteins, and the medication can pass across the blood-brain barrier.
- Metabolism: Mercaptopurine is extensively and quickly metabolized, with the liver playing a significant part in this process. By catalyzing thiol methylation, thiopurine S-methyltransferase (TPMT) transforms the medication into methyl-mercaptopurine, which is inert. Xanthine oxidase also plays a role in oxidation, converting Mercaptopurine into the inert form of 6-thiouric acid.
- Excretion: 46% of the removal process is made up of urine, which is the main route of excretion for Mercaptopurine and its metabolites. The medication is known for having a short half-life, measuring 21 minutes in children and 47 minutes in adults, with a clearance rate of 11 mL/min/kg. Additionally, dialyzable Mercaptopurine is not possible.
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- US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Purixan (mercaptopurine)
- https://www.ncbi.nlm.nih.gov/books/NBK557620/
- KD Tripathi. Essentials of Medical Pharmacology. Eighth Edition. New Delhi, India: Jaypee Brothers Medical Publishers; 2019
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/009053s040lbl.pdf
Published on: 28 Jan 2024 10:04 AM GMT