PURINETHOL 50 MG ( MERCAPTOPURINE ) 25 TABLETS

Dosing & Uses
Adult
Dosage Forms & Strengths
tablet
50mg
oral suspension
20mg/mL

• Acute Lymphatic Leukemia

Induction: 2.5 mg/kg PO qDay; usually 100-200 mg PO qDay in average adult (other agents preferred)  

May increase by 5 mg/kg/day after 4 weeks

Maintenance: 1.5-2.5 mg/kg PO qDay

Reduce dose by 75% if concomitant allopurinol administration

Reduce dose in renal impairment

• Crohn Disease (Off-label)

1-1.5 mg/kg PO qHS

Administration
Take on empty stomach to reduce risk of N/V

Other Information
Monitor: CBC, LFTs

Other Indications & Uses
AML

(Off-label): CML, Crohn's disease, ulcerative colitis, histiocytosis X

Interactions
All InteractionsSort By: 
Severity
Contraindicated (1)

febuxostat

Serious (30)
adenovirus types 4 and 7 live, oral
axicabtagene ciloleucel
BCG vaccine live
brexucabtagene autoleucel
ciltacabtagene autoleucel
deferiprone
etrasimod
human papillomavirus vaccine, nonavalent
idecabtagene vicleucel
influenza virus vaccine quadrivalent, adjuvanted
influenza virus vaccine quadrivalent, intranasal
influenza virus vaccine trivalent, adjuvanted
influenza virus vaccine trivalent, intranasal
lisocabtagene maraleucel
measles mumps and rubella vaccine, live
measles, mumps, rubella and varicella vaccine, live
meningococcal A C Y and W-135 polysaccharide vaccine combined
palifermin
pneumococcal vaccine 13-valent
ropeginterferon alfa 2b
rotavirus oral vaccine, live
smallpox and mpox (vaccinia) vaccine, live
tisagenlecleucel
tocilizumab
tofacitinib
tongkat ali
typhoid vaccine live
varicella virus vaccine live
yellow fever vaccine
zoster vaccine live

Monitor Closely (73)
acalabrutinib
adalimumab
alefacept
allopurinol
anakinra
anthrax vaccine
antithymocyte globulin equine
antithymocyte globulin rabbit
astragalus
azathioprine
basiliximab
belatacept
canakinumab
cholera vaccine
cyclosporine
dengue vaccine
denosumab
diphtheria & tetanus toxoids
diphtheria & tetanus toxoids/ acellular pertussis vaccine
diphtheria & tetanus toxoids/acellular pertussis/poliovirus, inactivated vaccine
doxorubicin
doxorubicin liposomal
echinacea
etanercept
everolimus
fingolimod
glatiramer
golimumab
haemophilus influenzae type b vaccine
hepatitis A vaccine inactivated
hepatitis a/b vaccine
hepatitis b vaccine
hydroxychloroquine sulfate
hydroxyurea
infliximab
influenza A (H5N1) vaccine
influenza A (H5N1) vaccine, adjuvanted
influenza virus vaccine quadrivalent
influenza virus vaccine quadrivalent, cell-cultured
influenza virus vaccine quadrivalent, recombinant
influenza virus vaccine trivalent
influenza virus vaccine trivalent, recombinant
isavuconazonium sulfate
Japanese encephalitis virus vaccine
leflunomide
maitake
meningococcal group B vaccine
methotrexate
muromonab CD3
mycophenolate
ocrelizumab
ocrelizumab/hyaluronidase
ofatumumab SC
olaparib
oxaliplatin
ozanimod
pneumococcal vaccine polyvalent
poliovirus vaccine inactivated
rabies vaccine
rabies vaccine chick embryo cell derived
siponimod
sipuleucel-T
sirolimus
tacrolimus
temsirolimus
tetanus toxoid adsorbed or fluid
trastuzumab
trastuzumab deruxtecan
typhoid polysaccharide vaccine
ublituximab
ustekinumab
valoctocogene roxaparvovec
zoster vaccine recombinant

Minor (5)
benazepril
maitake
taurine
vitamin A
vitamin E

Adverse Effects
>10%
Elevated LFT's (15%)

1-10%

Nausea (10%)

Vomiting (10%)

Stomatitis (3-10%)

Thrombocytopenia (3-10%)

Rash (1-3%)

Diarrhea (1-3%)

Dizziness (1-3%)

Alopecia (1-3%)

Leukopenia (1-3%)

Frequency Not Defined
Fatigue

Anorexia

Headache

Chills and fever

Chest pain

Mucositis

Upper respiratory infection

Cough

Ulceration of intestine

Ulcerative stomatitis

Myelosuppression

Decreased hematocrit

Hepatotoxicity

Decreased resistance to infections

Hyperuricemia

Nephrotoxicity

Increased risk of pancreatitis in pts with IBD

Hyperpigmentation of skin

Arthralgias

Eye discomfort

Tinnitus

Postmarketing Reports
Photosensitivity

Hypoglycemia

Portal hypertension

Macrophage activation syndrome

Urticaria

Hyperbilirubinemia

Bone marrow toxicity

Hyperuricemia and/or hyperuricosuria

Skin rashes and hyperpigmentation

Alopecia

Fever (rare)

Intrahepatic cholestasis of pregnancy (ICP)

Pellagra

Erythema nodosum

Warnings
Contraindications
None

Cautions
Renal impairment

Recommended that evaluation of hemoglobin or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained weekly while patient is on therapy

Macrophage activation syndrome (MAS) (hemophagocytic lymphohistiocytosis) a life-threatening disorder, may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD); there could potentially be an increased susceptibility for developing the condition with the use of mercaptopurine (an unapproved use); if MAS occurs, or is suspected, discontinue therapy; monitor for and promptly treat infections such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS

Drug fever very rarely reported; before attributing fever to drug, make every attempt to exclude more common causes of pyrexia, such as sepsis, in patients with acute leukemia

Mercaptopurine is immunosuppressive and may impair the immune response to infectious agents or vaccines; due to immunosuppression associated with maintenance chemotherapy for ALL, response to all vaccines may be diminished and there is a risk of infection with live virus vaccines; consult immunization guidelines for immunocompromised patients

Hepatotoxicity

• Mercaptopurine is hepatotoxic; there are reports of deaths attributed to hepatic necrosis associated with administration of the drug; hepatic injury can occur with any dosage but seems to occur with greater frequency when recommended dosage is exceeded; in some patients, jaundice has cleared following withdrawal of mercaptopurine and reappeared with rechallenge
• Usually, clinically detectable jaundice appears early in the course of treatment (1 to 2 months); however, jaundice has been reported as early as 1 week and as late as 8 years after starting mercaptopurine; the hepatotoxicity has been associated in some cases with anorexia, diarrhea, jaundice and ascites; hepatic encephalopathy has occurred; monitor serum transaminase levels, alkaline phosphatase, and bilirubin levels at weekly intervals when first beginning therapy and at monthly intervals thereafter
• Monitor liver tests more frequently in patients who are receiving therapy with other hepatotoxic products or with known pre-existing liver disease; withhold therapy at onset of hepatotoxicity
• Intrahepatic cholestasis of pregnancy (ICP) has been reported in patients with inflammatory bowel disease (off-labeled use); discontinue therapy if ICP develops during pregnancy

Myelosuppression

• The most consistent, dose-related adverse reaction is myelosuppression, manifested by anemia, leukopenia, thrombocytopenia, or any combination of these; monitor CBC and adjust dosage for excessive myelosuppression
• Bone marrow examination may be useful for evaluation of marrow status; decision to increase, decrease, continue, or discontinue a given dosage must be based upon degree of severity and rapidity with which changes are occurring; in many instances, particularly during induction phase of acute leukemia, complete blood counts will need to be done more frequently than once weekly in order to evaluate effect of therapy
• Myelosuppression can be exacerbated by coadministration with allopurinol, aminosalicylates or other products that cause myelosuppression; reduce dose by 75% (ie, give quarter dose) when used concurrently with allopurinol
• Increased risk of bone marrow toxicity; evaluate patients with repeated severe myelosuppression for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency; TPMT genotyping or phenotyping (red blood cell TPMT activity) and NUDT15 genotyping can identify patients who have reduced activity of these enzymes; patients with homozygous TPMT or NUDT15 deficiency require substantial dosage reductions of the drug
• Increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ; increased risk appears to be related to degree and duration of immunosuppression; discontinuation of immunosuppression reported to provide partial regression of lymphoproliferative disorder; a treatment regimen containing multiple immunosuppressants (including thiopurines) should be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities; a combination of multiple immunosuppressants, given concomitantly increases risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders

Hepatosplenic T-cell lymphomas

• Rare postmarketing cases reported primarily in adolescent and young adult patients with Crohn disease and ulcerative colitis treated with TNF blockers
• Reports have also included a patient being treated for psoriasis and 2 patients being treated for rheumatoid arthritis
• HSTCL is an aggressive, rare type of T-cell lymphoma (usually fatal)
• Most reported cases with TNF blockers have occurred with concomitant treatment with azathioprine or 6-mercaptopurine, although there have been cases reported receiving azathioprine or mercaptopurine alone
• The following HSTCL cases have been identified in the FDA Adverse Event Reporting System (AERS) database, the literature, and the HSTCL Cancer Survivors' Network: infliximab (20), etanercept (1), adalimumab (2), infliximab/adalimumab (5), certolizumab (0), golimumab (0), azathioprine (12), and mercaptopurine (3)

Pregnancy & Lactation
Pregnancy
Therapy can cause fetal harm when administered to a pregnant woman; pregnant women who receive mercaptopurine have an increased incidence of miscarriage and stillbirth; advise pregnant women of potential risk to fetus

Verify pregnancy status in females of reproductive potential prior to initiating therapy

Intrahepatic cholestasis of pregnancy (ICP) has been reported in patients with inflammatory bowel disease (off-labeled use); discontinue therapy if ICP develops during pregnancy

Reproductive potential

• Females: Advise females of reproductive potential to use effective contraception during treatment and for 6 months after last dose
• Males: Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with PURIXAN and for 3 months after the last dose

Infertility

• Females and males: Based on findings from animal studies, drug can impair female and male fertility; the long-term effects on female and male fertility, including the reversibility have not been studied

Animal data

• Drug was embryo-lethal and teratogenic in several animal species (rat, mouse, rabbit, and hamster) at doses less than recommended human dose

Lactation
There are no data on presence of mercaptopurine or metabolites in human milk, effects on breastfed child or on milk production; because of potential for serious adverse reactions in breastfed child, advise women not to breastfeed during treatment and for 1 week after last dose

Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.

Pharmacology
Mechanism of Action
Analog of naturally occurring purines hypoxanthine and guanine

Purine antagonist, antineoplastic

Absorption
Bioavailability: 5-37%

Peak Plasma Time: 2 hr

Onset: 2 hr

Duration: variable

Distribution
Protein Bound: 19%

Vd: 0.56-0.9 L/kg

Metabolism
GI mucosa, liver

Metabolites: 6-thiouric acid

Elimination
Half-Life: 21 minutes (children), 47 min (adult)

Clearance: 11 mL/min/kg

Excretion: urine

Dialyzable: no

Pharmacogenomics
6-mercaptopurine is activated by guanine phosphoribosyltransferase (HGPRT) to form thioinosine monophosphate (TIMP) and by kinase enzymatic pathways to form active 6-thioguanine nucleotides

Thiopurine S-methyltransferase (TPMT) inactivates 6-mercaptopurine

Although complete TPMT deficiency is rare in the general population (0.3%), TPMT screening should be performed prior to administration in all patients prescribed azathioprine or 6-mercaptopurine

With TPMT deficiency, a larger proportion of 6-mercaptopurine is converted to the cytotoxic 6-thioguanine nucleotide analogues, which can lead to bone marrow toxicity and myelosuppression

Alleles associated with decreased TPMT enzymatic activity are TPMT*2, TPMT*3A, and TPMT*3C

Genetic testing laboratories
The following companies currently offer testing for TPMT variants
Prometheus Labs (https://www.prometheuslabs.com/)
Arup Laboratories (https://www.aruplab.com/)

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