Mercaptopurine (6-MP) is a purine analog that interferes with DNA synthesis. It is used in the treatment of patients with ALL, APML, and inflammatory bowel diseases (ulcerative colitis and Crohn's disease).

Mercaptopurine Uses:

• Acute lymphoblastic leukemia:
  • It is used in the treatment of acute lymphoblastic leukemia (ALL), as part of a combination chemotherapy regimen.
• Off Label Use of Mercaptopurine in Adults:
  • In Acute promyelocytic leukemia as maintenance therapy.
  • In Crohn disease for management after surgical resection.
  • In Crohn's disease for remission maintenance or steroid-sparing therapy.
  • Lymphoblastic lymphoma
  • In Ulcerative colitis for remission induction.
  • In Ulcerative colitis for remission maintenance.

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Mercaptopurine Dose in Adults:

• Before taking the medicine mercaptopurine, some people need to be tested for certain genes: TPMT and NUDT15.
• If they have deficiencies in these genes, they could experience strong side effects from the regular dose of the medicine.
• So, if they have the deficiency, they need a lower dose to be safe.

Mercaptopurine Dose in the treatment of Acute lymphoblastic leukemia (ALL):

Standard Maintenance Treatment:

• Taken by mouth: 1.5 to 2.5 mg for every kilogram of body weight, once a day.
• The dose can be changed based on blood test results.

Off-label ALL dosing with other medicines:

• Early intensification: 60 mg for every square meter of body surface, daily, for the first 14 days.
• Interim maintenance: 60 mg per square meter of body surface, daily, for 70 days.
• Extended Maintenance: You can either take 50 mg three times a day for 2 years or 60 mg per square meter of body surface daily for 2 years from when you're diagnosed.

AALL0232 Treatment Plan (from Larsen 2016):

• For patients 30 years old or younger:
  • Consolidation Phase: 60 mg per square meter of body surface, daily, on days 1-14 and 29-42. This is combined with other medications.
  • Interim Maintenance 1 & 2: 25 mg per square meter of body surface, daily, for 56 days. Again, this is combined with other medications.
  • Maintenance Phase: 75 mg per square meter of body surface, daily, for the first 84 days in an 84-day cycle. This continues for 2 years for women and 3 years for men, starting from the beginning of Interim Maintenance I. The dose might be adjusted based on specific blood cell counts.

Mercaptopurine Dose in the treatment of Acute promyelocytic leukemia, maintenance (off-label):

For treating Acute Promyelocytic Leukemia (a specific type of leukemia), when using mercaptopurine as a maintenance treatment (and it's not the typical use):

• Take 60 mg of mercaptopurine for every square meter of your body surface, daily, for a year.
• You'll also be taking it with two other medications: tretinoin and methotrexate.

Mercaptopurine Dose in the treatment of Crohn disease, management after surgical resection (off-label):

Combination with Metronidazole:

• Take by mouth: 1.5 mg of mercaptopurine for every kilogram of your body weight, daily.
• This treatment lasts for about 18 months after your surgery.

Starting After Surgery:

• Take 50 mg of mercaptopurine by mouth, once a day.
• Begin this treatment right before leaving the hospital after surgery and continue for 24 months (or 2 years).

Mercaptopurine Dose in the treatment of Crohn disease (remission maintenance or steroid-sparing therapy) (off-label):

For treating Crohn's disease (to maintain remission or reduce the need for steroids):

• Take mercaptopurine by mouth at a dose ranging from 0.75 mg to 1.5 mg for every kilogram of your body weight, daily.
• This treatment is combined with another type of medicine called an anti-TNF agent (like adalimumab or infliximab).

Mercaptopurine Dose in the treatment of Lymphoblastic lymphoma (off-label):

For treating Lymphoblastic Lymphoma (not the standard treatment):

• Take 50 mg of mercaptopurine by mouth, three times a day.
• Continue this treatment for 2 years.

Mercaptopurine Dose in the treatment of Ulcerative colitis, remission induction (off-label):

For treating Ulcerative Colitis (to induce remission, and it's not the typical use):

• Start by taking 50 mg of mercaptopurine by mouth, once a day.
• Depending on how well you tolerate it, the dose can be increased up to 1.5 mg for every kilogram of your body weight, daily.

However, a caution:

• Using mercaptopurine alone (without other medications) is not advised for people with moderate to severe active ulcerative colitis.

Mercaptopurine Dose in the treatment of Ulcerative colitis, remission maintenance (off-label):

For maintaining remission in Ulcerative Colitis treatment (not the standard treatment):

• Take mercaptopurine by mouth at a dose ranging from 1 mg to 1.5 mg for every kilogram of your body weight, daily.

Adjusting Mercaptopurine Dosage Based on TPMT and/or NUDT15 Genetic Activity:

• Normal Activity (wild type):
  • No change needed to start.
  • Change the dose based on the medical condition.
  • If combining with other drugs, don't just focus on changing the mercaptopurine dose.
• Intermediate Activity (either TPMT or NUDT15):
  • Start with 30% to 80% of the typical dose.
  • If there's an issue with low blood cell counts (myelosuppression), mainly consider reducing mercaptopurine before other drugs.
• Very Low Activity (TPMT poor metabolizer):
  • For cancer: Start with a much lower dose (10 times less) and take it less often (3 times a week).
  • For other conditions: Think about using a different drug that isn't a thiopurine.
• Very Low Activity (NUDT15 poor metabolizer):
  • For cancer: Start with 10 mg for every square meter of body surface daily.
  • For other conditions: Consider a different drug that isn't a thiopurine.

Manufacturer's Recommendations:

• Some Activity Missing (heterozygous deficiency):
  • Adjust the dose based on how well it's tolerated.
  • Most can take the regular dose, but some might need less. If missing activity from both genes, might need a bigger dose reduction.
• Major Activity Missing (homozygous deficiency):
  • Take only 10% of the typical dose or even less.

If Taking Allopurinol with Mercaptopurine:

• It's better not to mix them.
• If you have to, take only 25% to 33% of the usual mercaptopurine dose.

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Mercaptopurine Dose in Childrens:

People who don't have much or any TPMT activity can have serious side effects from the regular dose of mercaptopurine. So, they might need a lower dose. It's a good idea to test for TPMT and another thing called NUDT15 before deciding on the dose. For kids, doses are given based on their body size or weight, so be very careful.

Mercaptopurine Dose in the treatment of Acute lymphoblastic leukemia (ALL):

Standard Risk Treatment:

• Age: Children from 1 to less than 10 years old.
• Dose: Take 75 mg for every square meter of body size, once daily.
• When and How Long:
  • During the Consolidation, Interim Maintenance I, and Maintenance phases.
  • Maintenance lasts 2 years for girls and 3 years for boys from the start of Interim Maintenance I.
• Combo with Other Drugs: Used alongside vincristine, steroids, and methotrexate (either by mouth or injection into the spine).
• Adjustment: During Maintenance, the doses of methotrexate and mercaptopurine might be changed to keep white blood cell counts in a specific range (usually 1,000 to 2,000 per cubic millimeter, but this can change based on the treatment plan).

High-Risk Treatment:

• Age: Children from 1 to less than 10 years old.
• Doses:
  • Consolidation: Take 60 mg for every square meter of body size, once daily, on certain days (days 1-14 and 29-42 in a 56-day cycle).
  • Interim Maintenance: 25 mg for every square meter of body size, once daily, for 56 days.
  • Maintenance Phase: 75 mg for every square meter of body size, once daily, for the first 84 days in an 84-day cycle.
• When and How Long:
  • Maintenance lasts 2 years for girls and 3 years for boys from the start of Interim Maintenance I.
• Combo with Other Drugs: Used with several other medications like vincristine, steroids, methotrexate (by mouth or injection into the spine), and others.
• Adjustment: During Maintenance, the doses of methotrexate and mercaptopurine might be adjusted to keep white blood cell counts in a specific range (usually 1,000 to 2,000 per cubic millimeter, but this can vary based on the treatment plan).

Mercaptopurine Dose in the treatment of Acute promyelocytic leukemia (APL):

Combination with Tretinoin:

• Age: Children and teens up to 14 years old.
• Dose: Take 100 mg for every square meter of body size, once daily, for 14 days. This is in a 28-day cycle.
• Duration: Repeat the cycle every 28 days for 2 years.

Combination with Tretinoin and Methotrexate (by Ortega 2005, PETHEMA Group):

• Age: Children and teens up to 17 years old.
• Dose: Take 50 mg for every square meter of body size, once daily, for 2 years.
• Adjustments: If white blood cell count (WBC) drops to certain levels, decrease the dose or stop the medication.

Combination with Tretinoin and Methotrexate (by Powell 2010, North American Leukemia Intergroup Study):

• Age: Teens 15 years and older.
• Dose: Take 60 mg for every square meter of body size, once daily, for 1 year.

Mercaptopurine Dose in the treatment of Autoimmune hepatitis: 

For children and teenagers:

• Dose: Take 1.5 mg of mercaptopurine for every kilogram of body weight, once daily.
• Combination: This is used together with another medicine called prednisone.
• Note: Mercaptopurine isn't the first choice for treatment. It's usually given to patients who can't handle another drug called azathioprine.

Mercaptopurine Dose in the treatment of Inflammatory bowel disease (eg, Crohn disease, ulcerative colitis):

Dosing for Children and Teens:

• General Dose: 1 to 1.5 mg of mercaptopurine for every kilogram of body weight, taken daily by mouth.

For Younger Kids (6 years or below):

• They might need higher doses to get better. Some studies showed that giving about 1.68 mg for every kilogram of body weight helped more of them get better.
• However, the dose shouldn't go above 2.4 mg for every kilogram of body weight daily.

Starting Treatment:

• Begin with a max of 50 mg for the first week.
• If the kid doesn't have any side effects, then you can increase to the full suggested dose.

Dosing adjustment with concurrent allopurinol:

If Taken with Allopurinol:

• For Children and Teens: Reduce the mercaptopurine dose. How much you reduce it can vary based on specific treatment plans.

Adjustments for TPMT and/or NUDT15 Genetic Activity:

• Some Activity Missing (heterozygous deficiency):
  • Adjust the dose based on how well it's tolerated.
  • Many with this deficiency can take the regular dose, but some might need less. If missing activity from both genes, you might need a bigger dose reduction.
  • For those with lower TPMT activity: Start with 30% to 70% of the regular dose. Adjust if needed, especially if there's a drop in blood cells (myelosuppression). If adjustments are needed, the final dose might be around 40% less than what's typically given.
• Major Activity Missing (homozygous deficiency):
  • Take only 10% of the typical dose or even less.
  • For those with very low TPMT activity and treating cancer: Start with a much smaller dose (10 times less) and take it less often (3 times a week). Adjust as needed, especially watching for blood cell counts. If not treating cancer, think about using a different drug that isn't a thiopurine.
• Normal Activity (homozygous wild type):
  • No change needed to start.
  • Adjust if needed, but not just focusing on mercaptopurine if other medicines are involved.

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Mercaptopurine Pregnancy Category: D

• Taking mercaptopurine during pregnancy can harm the baby.
• There have been reports of miscarriages, especially when taken during the first three months.
• There are also concerns with taking it later in pregnancy.
• If you can have children and are on this medication, it's important to prevent pregnancy.

Use of mercaptopurine during breastfeeding

• Mercaptopurine is what azathioprine turns into in the body.
• If a mother takes azathioprine, mercaptopurine can show up in her breast milk.
• However, it's not clear how much mercaptopurine might be in breast milk if taken directly.
• The medicine's maker suggests that if a mother needs to take mercaptopurine while breastfeeding, she should consider the benefits of the medicine to her versus the potential risks to the baby.

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Dose in Kidney Disease:

• For patients with kidney problems, start mercaptopurine at a lower dose or take it less often (maybe every 36 to 48 hours) to prevent too much from building up in the body.
• However, the medicine's maker doesn't give a specific adjusted dose for these patients.

Dose in Liver disease:

• For patients with liver problems, it might be a good idea to start mercaptopurine at a lower dose and watch closely for any bad reactions.
• However, the medicine's label doesn't give a specific adjusted dose for these situations.

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Side effects of Mercaptopurine:

• Central Nervous System:
  • Malaise
  • Drug Fever
• Dermatologic:
  • Skin Rash
  • Hyperpigmentation
  • Urticaria
  • Alopecia
• Endocrine & Metabolic:
  • Hyperuricemia
• Gastrointestinal:
  • Anorexia
  • Diarrhea
  • Nausea
  • Vomiting
  • Oral Lesion
  • Pancreatitis
  • Cholestasis
  • Mucositis
  • Sprue-Like Symptoms
  • Stomach Pain
  • Ulcerative Bowel Lesion
• Genitourinary:
  • Oligospermia
  • Renal Toxicity
  • Uricosuria
• Hematologic & Oncologic:
  • Bone Marrow Depression
  • Anemia
  • Granulocytopenia
  • Hemorrhage
  • Hepatosplenic T-Cell Lymphomas
  • Leukopenia
  • Lymphocytopenia
  • Metastases
  • Neutropenia
  • Thrombocytopenia
• Hepatic:
  • Hyperbilirubinemia
  • Increased Serum Transaminases
  • Ascites
  • Hepatic Encephalopathy
  • Hepatic Fibrosis
  • Hepatic Injury
  • Hepatic Necrosis
  • Hepatomegaly
  • Hepatotoxicity
  • Intrahepatic Cholestasis
  • Jaundice
  • Toxic Hepatitis
• Immunologic:
  • Immunosuppression
• Infection:
  • Infection
• Respiratory:
  • Pulmonary Fibrosis

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Contraindications to Mercaptopurine:

Don't use mercaptopurine if:

• You're allergic to it or anything in the medicine.
• The illness didn't get better with mercaptopurine before.

Warnings and precautions

Suppression of bone marrow

• This drug can lower the number of white and red blood cells and platelets in your body.
• This might be due to the drug or the illness getting worse.
• These effects can take time to show up.
• The inside of bones, called bone marrow, might not be producing enough cells (or it might look normal).
• Keep an eye on blood cell counts.
• If certain cells drop too low, the drug dose might need to be changed.
• Be on the lookout for signs of bleeding (because of low platelets) or infections (because of low white blood cells).
• If these blood cell issues are very bad or keep happening, it might be due to certain genes like TPMT or NUDT15 not working well.
• People with these genes not working well might need a much lower dose of the drug.
• Tests can check for these gene issues.

Hepatotoxicity

• This medicine can harm the liver.
• Some signs include yellowing of the skin (jaundice), swelling in the abdomen (ascites), and liver damage.
• It can happen with any dose, but it's more common with higher doses.
• Jaundice might show up early, about 1 to 2 months into treatment.
• If you stop the medicine, jaundice might go away, but it can come back if you start the medicine again.
• Watch liver tests often, especially when starting treatment, and regularly afterward.
• If you're taking other drugs harmful to the liver or have liver issues, be cautious.
• If you show signs of liver problems, like jaundice or belly pain, stop the medicine

Immunosuppression

• Mercaptopurine can weaken the immune system.
• This means the body might not fight off infections as well, and there's a higher chance of getting sick.
• Usual signs like fever and high white blood cell count might not show up if there's an infection.
• Instead, feeling very tired or confused might be the main signs.
• Always be alert for any signs of illness.

Macrophage activation Syndrome:

• There's a severe condition called Macrophage Activation Syndrome (MAS) that can happen, especially in people with autoimmune diseases like inflammatory bowel disease.
• Taking mercaptopurine for these diseases (which isn't its main use) can make someone more likely to get MAS.
• If someone seems to have MAS, stop taking mercaptopurine right away.
• Watch out for and quickly treat infections like Epstein-Barr virus and cytomegalovirus, as they can trigger MAS.

Photosensitivity

• Avoid spending a lot of time in the sun, as this medicine can make the skin more sensitive to sunlight.

Secondary malignancy

• Medicines like mercaptopurine, which weaken the immune system, can increase the risk of getting certain cancers.
• Some people using mercaptopurine (and similar drugs) have developed a rare but deadly type of white blood cell cancer.
• This risk is even higher if they were also using certain other medications.
• Other cancers, like skin cancers and a type of cancer affecting the cervix, have been seen in people using medicines like mercaptopurine.
• The longer and stronger the immune system is suppressed, the higher the risk.
• Some of these cancer conditions might get a bit better if the medication is stopped.

Renal impairment

• If someone has kidney problems, they might need a lower dose of mercaptopurine or take it less often.
• Drinking plenty of water and taking other medicines to lower uric acid levels might help reduce some kidney-related side effects.

TPMT/NUDT15 deficiency

• Some people have genetic differences that affect how their bodies handle drugs like mercaptopurine.
• These differences might make them more likely to get severe side effects, especially on normal doses.
• People with these differences might need a lot less of the drug to avoid bad side effects.
• Genetic tests can help identify who might be at risk.
• Doctors might suggest lower starting doses for those with these differences.
• In some cases, if the risk is very high, different medications might be considered.
• These genetic differences are more common in certain ethnic groups.

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Monitoring parameters:

Regular Tests and Observations:

• Blood Tests:
  • Check CBC (Complete Blood Count) with details weekly at the start. If there are concerns, you might need the test more often.
  • Bone marrow exams are useful for checking on leukemia and seeing how many cells the bone marrow is making, especially if blood counts are consistently low.
  • Liver tests should be done weekly at the start and then monthly. Check more often if using other liver-harming medicines or if there were liver issues before.
  • Keep an eye on kidney function and test the urine.
• Signs to Watch For:
  • Be alert for signs of a rare immune system problem called macrophage activating syndrome.
  • Watch out for reactions from sunlight exposure.
  • Make sure the medicine is being taken as directed.

Specific Genetic Tests:

• TPMT Test:
  • Some people have a gene that changes how they react to mercaptopurine. Consider getting tested if blood counts are unusually low and not getting better even with a lower drug dose.
• NUDT15 Test:
  • This is another gene that can affect reactions to the drug. Consider getting tested if there are severe issues with blood cell counts.

For Crohn's Disease or Ulcerative Colitis:

• Blood Tests:
  • Check CBC with details weekly for the first month, every two weeks for the second month, and then every 1 to 2 months.
  • Check liver function tests every 3 months.
• Signs to Watch For:
  • Be alert for signs of cancer like an enlarged spleen or liver, belly pain, constant fever, night sweats, and weight loss.

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How to administer Mercaptopurine?

Best Practices:

• Empty Stomach: It's best to take it without having eaten recently.
• Avoid Milk: If you can, don't have it with dairy like milk.
• Consistency: Try to take the medicine at the same time every day.

Adjustments:

• If it's hard to take the medicine on an empty stomach or to avoid dairy, it's okay to make changes, like taking it with food. What's most important is taking the medicine regularly.
• Research showed that when people take the medicine regularly, the time of day, or taking it with food or milk, didn't impact the medicine's effectiveness in treating a type of cancer called ALL.

Using the Suspension Form:

• Shake Well: The liquid is thick, so shake it hard for at least 30 seconds to mix it up.
• Measuring: Use the syringes provided to get the right dose. There's a 1 mL and a 5 mL syringe included.
• Training: Make sure patients or caregivers know how to measure the right dose, how to handle and store the medicine, and how to clean up any spills.
• Use Quickly: Once opened, use the suspension within 8 weeks.

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Mechanism of action of Mercaptopurine:

Mercaptopurine is a type of medicine that fights against certain processes in the body:

• Purine Antagonist: It works against purines, which are building blocks for DNA and RNA, the genetic materials in cells.
• DNA and RNA Inhibition: Mercaptopurine stops the creation of DNA and RNA, which are essential for cells to grow and function properly.
• Impersonating Molecules: It tricks cells by acting like other molecules, getting incorporated into DNA and RNA. This tricks the cells into thinking they're building with the right materials.
• Blocking Synthesis: Once it's in the DNA and RNA, it blocks their construction, preventing the cells from making new genetic material.
• Cell Cycle Impact: Mercaptopurine specifically affects cells in the S phase of their growth cycle, when they're actively replicating their DNA.

Absorption:

• Not all of it is fully absorbed. About half of a dose gets absorbed into the body.
• The liquid form (suspension) is absorbed more (34% higher) than the tablet form.

Distribution:

• Volume (V): It spreads out in the body more than just the water in our bodies.
• It doesn't get into the brain very well.

Binding:

• About 19% of mercaptopurine binds to proteins in the blood.

Metabolism (how the body breaks it down):

• It's mostly broken down in the liver and also a bit in the lining of our guts.
• In the liver, it gets changed by enzymes called xanthine oxidase and thiopurine methyltransferase into different forms.
• Some of these forms are inactive and don't do anything.

How Long it Lasts:

• Tablets: It lasts about 21 minutes in children and 47 minutes in adults.
• Suspension: It lasts about 2 hours.

When it Peaks:

• The highest amount in the blood is reached within 2 hours of taking it.

Excretion (how the body gets rid of it):

• About 46% of it is removed from the body through urine. This includes both unchanged mercaptopurine and its changed forms.

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International Brand Names of Mercaptopurine:

• Purixan
• Purinethol
• 6-MP
• Allmercap
• Capmerin
• Empurine
• Leukin
• Mercaptopurina
• Merkaptopurin
• Merpurin
• Puri-Nethol
• Puri-nethol
• Purinethjol
• Purinethol
• PuriNethol
• Purinetone
• Varimer
• Xaluprine

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Mercaptopurine Brand Names in Pakistan:

Mercaptopurine (Monohydrate) Tablets 50 mg in Pakistan
Mercaprine	Pharmedic (Pvt) Ltd.
Mercaptepurine	Lahore Chemical & Pharmaceutical Works (Pvt) Ltd
Purinetone	Al-Habib Pharmaceuticals.