Purixan

• Nova Products

Serious side effects have been reported with mercaptopurine including the following:

• lowered blood counts. This is medically known as bone marrow suppression. Bone marrow suppression can lead to thrombocytopenia, anemia, and leukopenia.
  • thrombocytopenia. This is a condition in which your blood has a lower than normal number of blood cell fragments called platelets. Tell your healthcare provider right away if you have the following signs and symptoms of thrombocytopenia:
    • mild to serious bleeding
    • purple, brown, and red bruises (purpura)
    • small red or purple dots on your skin (petechiae)
    • prolonged bleeding, even from minor cuts
    • bleeding or oozing from the mouth or nose, especially nosebleeds or bleeding from brushing your teeth
    • abnormal vaginal bleeding (especially heavy menstrual flow)
    • blood in the urine or stool or bleeding from the rectum. Blood in the stool can appear as red blood or as a dark, tarry color. Taking iron supplements also can cause dark, tarry stools.
    • headaches and other neurological symptoms. These problems are very rare, but you should discuss them with your doctor.
  • anemia. This is a condition in which your blood has a lower than normal number of red blood cells. Tell your healthcare provider right away if you have the following signs and symptoms of anemia:
    • shortness of breath
    • dizziness
    • headache
    • coldness in the hands and feet
    • pale skin
    • chest pain
  • leukopenia. This is a condition when there are a low number of white blood cells in your body. These cells help fight infections. You may become more susceptible to infections and even to negative reactions of live vaccines if you are taking mercaptopurine. Tell your healthcare provider if you are feeling “under the weather” or are running a fever. Also, let your healthcare provider know if you are scheduled to receive a vaccination, as your response to vaccines may be diminished and live vaccinations can make you sick.
• a decline in liver function. Tell your healthcare provider if you have any signs or symptoms of liver damage, which include the following:
  • yellowing of the skin or eyes
  • nausea
  • vomiting
  • fatigue
  • itching
• intestinal ulceration. Tell your healthcare provider if you have any signs or symptoms such as nausea, vomiting, bleeding from any site, or symptoms suggestive of anemia.

Do not take mercaptopurine if you:

• are allergic to mercaptopurine or to any of its ingredients
• have already taken this drug and it has shown to be ineffective
• have already taken thioguanine (Tabloid, 6-TG, 6-Thioguanine) and it has shown to be ineffective

You should not use mercaptopurine if you have ever used mercaptopurine or thioguanine (Tabloid) and they were not effective in treating your condition.

Some people using mercaptopurine have developed a rare fast-growing type of lymphoma (cancer). This condition affects the liver, spleen, and bone marrow, and it can be fatal.

Call your doctor at once if you have symptoms of lymphoma, such as: fever, night sweats, weight loss, tiredness, feeling full after eating only a small amount, pain in your upper stomach, easy bruising or bleeding, dark urine, or jaundice (yellowing of the skin or eyes).

You should not use mercaptopurine if you are allergic to it, or if you have ever used mercaptopurine or thioguanine (Tabloid) and they were not effective in treating your condition.

Some people using mercaptopurine have developed a rare fast-growing type of lymphoma (cancer). This condition affects the liver, spleen, and bone marrow, and it can be fatal. This has occurred mainly in teenagers and young adults using mercaptopurine or similar medicines to treat Crohn's disease or ulcerative colitis.

However, people with autoimmune disorders (including rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, and psoriasis) may have a higher risk of lymphoma. Talk to your doctor about your individual risk.

To make sure mercaptopurine is safe for you, tell your doctor if you have:

• liver disease;

• kidney disease;

• any type of viral, bacterial, or fungal infection; or

• ulcerative colitis (treated with mesalamine, sulfasalazine, or similar medicines).

Do not use mercaptopurine if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether mercaptopurine passes into breast milk or if it could harm a nursing baby. You should not breast-feed while taking mercaptopurine.

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood tests may be needed to check for unwanted effects. Genetic testing may also be performed to check your levels of thiopurine S-methyltransferase (an enzyme needed to metabolize mercaptopurine).

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant during therapy. If you think you have become pregnant while using this medicine, tell your doctor right away.

Mercaptopurine can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
• Check with your doctor immediately if you notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.
• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
• Avoid contact sports or other situations where bruising or injury could occur.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.

While you are being treated with mercaptopurine, and after you stop treatment with it, do not have any immunizations (vaccines) without your doctor's approval. Mercaptopurine may lower your body's resistance and the vaccine may not work as well or you might get the infection the vaccine is meant to prevent. In addition, you should not be around other persons living in your household who receive live virus vaccines because there is a chance they could pass the virus on to you. Some examples of live vaccines include measles, mumps, influenza (nasal flu vaccine), poliovirus (oral form), rotavirus, and rubella. Do not get close to them and do not stay in the same room with them for very long. If you have questions about this, talk to your doctor.

This medicine may increase your risk of getting certain types of cancer, including skin cancer and cervical cancer. Some teenagers and young adults with Crohn's disease or ulcerative colitis developed a rare type of cancer called hepatosplenic T-cell lymphoma (HSTCL). Check with your doctor right away if you have unusual bleeding, bruising, or weakness, swollen lymph nodes in the neck, underarms, or groin, or unexplained weight loss.

This medicine may cause a life-threatening condition called macrophage activation syndrome (MAS). This usually occurs in patients with an autoimmune disease (eg, inflammatory bowel disease) or virus infection (eg, Epstein-Barr, cytomegalovirus), and must be treated immediately. Tell your doctor right away if you have a fever, cough that does not go away, redness in one part of your body, or warm feeling or swelling of your skin.

This medicine may make your skin more sensitive to sunlight. Wear sunscreen. Do not use sunlamps or tanning beds.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• It is used to treat a type of leukemia.
• It may be given to you for other reasons. Talk with the doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Very loose stools (diarrhea).
• Very upset stomach or throwing up.
• Change in color of skin.
• Redness or white patches in mouth or throat.
• Feeling very tired or weak.
• Shortness of breath.
• Very bad belly pain or soreness.
• A skin lump or growth.
• Very bad and sometimes deadly liver problems have happened with this medicine. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.

Mercaptopurine, a nucleoside metabolic inhibitor, known chemically as 1,7-dihydro-6H-purine-6-thione monohydrate, is an analogue of the purine bases adenine and hypoxanthine. Mercaptopurine is a yellow, odorless or practically odorless, crystalline powder with a molecular formula of C5H4N4S•H2O and a molecular weight of 170.20 as a monohydrate. The structural formula is:

Purixan (mercaptopurine) oral suspension is supplied for oral administration and contains 2000 mg/100 mL (20 mg/mL) of mercaptopurine. The suspension also contains the following inactive ingredients: xanthan gum, aspartame, concentrated raspberry juice, sucrose, ethyl parahydroxybenzoate sodium, methyl parahydroxybenzoate sodium, potassium sorbate, sodium hydroxide and purified water. Purixan is a pink to brown viscous suspension. In addition, a press-in bottle adapter and two oral dispensing syringes (one 1 mL and one 5 mL) are provided.

Mechanism of Action

Mercaptopurine activation occurs via hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) and several enzymes to form 6-thioguanine nucleotides (6-TGNs). Incorporation of 6-TGN into nucleic acids (instead of purine bases) results in cell-cycle arrest and cell death. Mercaptopurine competes with hypoxanthine and guanine for HGPRTase and is itself converted to thioinosinic acid (TIMP). This intracellular nucleotide inhibits several reactions involving inosinic acid (IMP), including the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP). In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. Both TIMP and MTIMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. Some mercaptopurine is converted to nucleotide derivatives of 6-thioguanine (6-TG) by the sequential actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase, converting TIMP to thioguanylic acid (TGMP).

Pharmacokinetics

Absorption and Bioavailability
Clinical studies have shown that the absorption of an oral dose of mercaptopurine in humans is incomplete and variable, averaging approximately 50% of the administered dose. The factors influencing absorption are unknown.

Following a single 50 mg dose of Purixan under fasting conditions the median (range) AUC was 136 h*ng/mL (74.2-264.8 h*ng/mL) and Cmax was 95 ng/mL (39.5-204 ng/mL).

Distribution
The volume of distribution usually exceeded that of the total body water. There is negligible entry of mercaptopurine into cerebrospinal fluid.

Metabolism
Mercaptopurine is inactivated via two major pathways. One is thiol methylation, which is catalyzed by the polymorphic enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-mercaptopurine. The second inactivation pathway is oxidation, which is catalyzed by xanthine oxidase. The product of oxidation is the inactive metabolite 6-thiouric acid.

Elimination
Following administration of Purixan, the elimination half-life (t1/2) was approximately 2 hours.

After oral administration of mercaptopurine, urine contains intact mercaptopurine, thiouric acid (formed by direct oxidation by xanthine oxidase, probably via 6-mercapto-8-hydroxypurine), and a number of 6-methylated thiopurines. In one subject, a total of 46% of the dose could be accounted for in the urine (as parent drug and metabolites) in the first 24 hours.

Pharmacogenomics

TPMT enzyme activity is highly variable in patients because of a genetic polymorphism in the TPMT gene. For Caucasians and African Americans, approximately 0.3% (1:300) of patients have two non-functional alleles (homozygous-deficient) of the TPMT gene and have little or no detectable TMPT activity. Approximately 10% of patients have one TPMT non-functional allele (heterozygous) leading to low or intermediate TPMT activity and 90% of patients have normal TPMT activity with two functional alleles.

Homozygous-deficient patients with little or no detectable TPMT activity, if given usual doses of mercaptopurine, accumulate excessive cellular concentrations of active 6-TGNs predisposing them to mercaptopurine toxicity. Heterozygous patients with low or intermediate TPMT activity accumulate higher concentrations of active 6-TGNs than patients with normal TPMT activity and are more likely to experience mercaptopurine toxicity [see Warnings and Precautions (5.1)].

TPMT genotyping or phenotyping (red blood cell TPMT activity) can identify patients who are homozygous deficient or have low or intermediate TPMT activity.

TPMT Testing
Genotypic and phenotypic testing of TPMT status are available. Genotypic testing can determine the allelic pattern of a patient. Currently, 3 allelesTPMT*2, TPMT*3A and TPMT*3C account for about 95% of individuals with reduced levels of TPMT activity. Individuals homozygous for these alleles are TPMT deficient and those heterozygous for these alleles have variable TPMT (low or intermediate) activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in erythrocytes and can also be informative. Caution must be used with phenotyping since some coadministered drugs can influence measurement of TPMT activity in blood, and recent blood transfusions will misrepresent a patient’s actual TPMT activity.

Applies to mercaptopurine: oral suspension, oral tablet

Along with its needed effects, mercaptopurine (the active ingredient contained in Purixan) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking mercaptopurine:

• Black, tarry stools
• clay colored stools
• cough or hoarseness
• dark urine
• decreased appetite
• fever or chills
• headache
• loss of appetite
• lower back or side pain
• nausea, vomiting
• painful or difficult urination
• pinpoint red spots on the skin
• rash, itchy skin
• stomach pain or tenderness
• swelling of the feet or lower legs
• unusual bleeding or bruising
• unusual tiredness or weakness
• yellow eyes or skin

• Bleeding gums
• chest pain
• joint pain
• pale skin
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• swollen glands
• trouble with breathing upon exertion

• Constipation
• diarrhea
• heartburn
• indigestion
• joint pain, stiffness, or swelling
• stomach cramping or burning
• vomiting of blood or material that looks like coffee grounds

Some side effects of mercaptopurine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Darkening of the skin
• headache

• Hair loss or thinning of the hair
• low sperm count