ZC 59 pill
ZC 59 pill is an imprint of Azathioprine 50 mg tablet.
Each tablet of azathioprine that is not coated and designed for oral use has 50 mg of Azathioprine. Furthermore, every tablet has these inactive components: croscarmellose, lactose monohydrate, magnesium Stearate povidone, and starch.
Azathioprine is chemically 6-[(1-methyl-4-nitro-1H-imidazole-5-yl)thio]-1H-purine. The chemical formula for Azathioprine is:
This is an imidazolyl derivative 6-mercaptopurine. Its biological properties are like those of the compound that is its parent.
Azathioprine, USP is a mild yellow powder with no odour. Insoluble in water. It is dissolvable in alkali dilute hydroxides only sparingly dissolves in mineral acids that are dilute extremely solubilized in alcohol and chloroform. Its sodium salt can be sufficiently soluble to form 10 mg/mL solution in water that is solid for 24 hours at temperatures ranging from 59deg or 77degF (15deg up to 25degC). Azathioprine is stable in solutions at pH neutral or acid, however, hydrolysis to mercaptopurine takes place with excess sodium hydroxide (0.1N) and is most noticeable when the temperature is heated. The conversion to mercaptopurine can also occur when Sulfhydryl substances like glutathione, cysteine and hydrogen sulfur.
Azathioprine is well-absorbed following oral administration. The peak in serum radioactivity occurs between 2 to 1 hour after the administration of the oral administration of 35S-azathioprine. It decays to the half-life of five hours. This is not an estimation for the duration of half-life azathioprine however, it represents the rate of decay of all 35S-containing metabolites in the drug. Due to its massive metabolic processes, just a small portion of the radioactivity is found in the form of azathioprine. The usual doses result in high levels in the blood of the azathioprine as well as mercaptopurine, derived from it. These levels are extremely low (<1 mg/mL). The blood levels have no predictors of therapy because the intensity and duration of the clinical effects are correlated with the levels of thiopurine in the tissues, not levels of the drug in plasma. Azathioprine and mercaptopurine have a moderate affinity to serum proteins (30 %) and are dialyzable in part.¶
Azathioprine is converted to 6-mercaptopurine (6-MP). Both compounds are eliminated rapidly from the blood and are then oxidized or methylated in erythrocytes as well as the liver. No azathioprine or mercaptopurine is detected in urine after eight hours. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites. Its cytotoxicity azathioprine is partly due in part, to DNA synthesis by incorporation.
6-MP undergoes two major inactivation routes. One of them is thiol-methylation, which is catalyzed through the enzyme called thiopurine Smethyltransferase (TPMT) and results in the inactive compound 6-MeMP, also known as methyl-6 (6-MeMP). Another pathway for activation is oxidation. It is caused by xanthine oxidase (XO) to produce 6-thiouric acid. Nucleotide diphosphatase (NUDT15) enzyme is involved in the conversion of the 6-TGNs into monophosphates that are inactive. TPMT activity is in inverse correlation with the levels of 6-TGN in erythrocytes, and likely other hematopoietic tissues as these cells exhibit negligible xanthine antioxidant (involved in another inactivation pathway) functions.
Genetic polymorphisms can affect TPMT as well as NUDT15 activity. Numerous studies have shown that those with lower NUDT15 or TPMT activities, taking the usual doses of azathioprine or 6-MP, have high levels of active 6-TGNs. They also are at a higher risk of developing severe myelosuppression. Due to the potential for toxicities, patients suffering from NUDT15 or TPMT deficiencies require alternate treatment or dose adjustments
The inhibition of xanthine oxidase (XO) could result in higher concentrations in plasma of azathioprine or its metabolites, leading to toxic effects. The proportions of metabolites vary in each patient and, therefore, could account for the varying duration and intensity of the effects. Renal clearance is not crucial in determining biochemical efficacy or toxicities through dose reduction is often practised in patients suffering from low renal function.
The application of azathioprine in the inhibition of rejection of renal homografts is well established, but the mechanism(s) that trigger this effect is a bit hazy. The drug reduces hypersensitivities that are cell-mediated and triggers a variety of changes in the production of antibodies. The inhibition of T-cell-mediated effects, as well as suppression of T-cells, is dependent on the time-dependent relationship with the antigenic stimulus or engraftment. This agent isn’t very effective on graft rejections that have been established or secondary reactions.
Changes in certain immune functions or immune system responses in recipients of transplants are not easily correlated to the immunosuppression caused through the azathioprine. Patients with the subnormal immune response to vaccines, insufficient amounts of T-cells and abnormal phagocytosis of peripheral blood cells. However, their mitogenic reactions as well as serum immunoglobulins and secondary antibody reactions are typically normal.
Azathioprine is a drug that reduces manifestations of disease as well as the underlying pathology in the animal models of autoimmune disease. As an example, the severity of arthritis in adjuvant forms is diminished by azathioprine.
The mechanisms through which azathioprine can cause autoimmune disorders aren’t fully understood. Azathioprine is an immunosuppressive drug, resulting in delayed hypersensitivity, and cellular tests for cytotoxicity are reduced to a greater extent than antibody responses. In the model of rat adjuvant arthritis, the drug is demonstrated to block lymph node hyperplasia that is the precursor to the onset of symptoms in the course of the disease. The immunosuppressive, as well as therapeutic effects observed in animal models, are influenced by dose. Azathioprine is regarded as to be a slow-acting drug, and its effects can persist even after the drug is taken off.
INDICATIONS AND USAGE
Azathioprine tablets USP can be used as an adjunct to prevent of rejection in the process of renal homotransplantation. It’s also recommended for the treatment of active rheumatoid arthritis to lessen the signs and symptoms.
Azathioprine tablets USP can be used as an aid in the treatment of rejection during homotransplantation of the kidney. Experiments with more than 16,000 transplants have shown a 5-year survival rate for patients of 35%-55% however, it is contingent on the donor match, donor HLA antigens as well as anti-donor or anti-B-cell alloantigen antibodies, and other factors. The impact of the azathioprine tablets on these factors has not been evaluated in controlled studies.
Azathioprine tablets USP can be used to treat active Rheumatoid Arthritis (RA) to decrease symptoms and signs. Aspirin, non-steroidal anti-inflammatory medications and/or low dose glucocorticoids could be taken in conjunction with tablets containing azathioprine. The combination of azathioprine tablets in conjunction with anti-rheumatic medicines that modify the course of disease (DMARDs) is not examined for added benefits or unanticipated adverse side effects. The combination of azathioprine tablets and these drugs is not advised.
Azathioprine tablets are not recommended for patients with hypersensitivity to the medication. Azathioprine tablets should not be used in treating rheumatoid arthritis during pregnancy women. Patients who have had rheumatoid arthritis before being treated with alkylating drugs (cyclophosphamide chlorambucil, melphalan, cyclophosphamide or other) could be at a high chance of developing cancer if treated by tablets containing azathioprine.
Malignancy Patients taking immunosuppressants such as azathioprine are at a higher risk of developing lymphoma as well as other malignancies, especially on the skin. The physician should inform patients of the possibility of developing malignancy when taking use of azathioprine. Like all patients who are at a high risk of developing skin cancer exposure to UV and sunlight light should be minimized with protective attire and sunscreen that has a high protective factor.
Patients of renal transplants are believed to be a likelihood of malignancy, particularly skin cancers and reticulum cells also known as lymphomatous tumours. The risk of lymphomas after transplantation can be higher when patients undergo intensive treatment with immunosuppressive medications such as azathioprine. So, treatment with immunosuppressive drugs must be kept at most effective levels.
There is information available about the possibility of malignancy arising from the usage of azathioprine for Rheumatoid Arthritis. It’s not been identified the precise cancer risk associated with azathioprine. The evidence suggests that the risk could be higher in those suffering from rheumatoid joint however, it is lower than transplant recipients. But, acute myelogenous leukemia and the development of solid tumours have been identified in patients suffering from rheumatoid arthritis who have been treated with Azathioprine.
Inflammatory Bowel Disease
Postmarketing cases of hepatosplenic-type T-cell lymphoma (HSTCL) which is the rarest form of T-cell lymphoma been reported by patients receiving Azathioprine. These cases have an extremely aggressive course of the disease and were fatal. The majority of cases reported are in patients suffering from ulcerative colitis or Crohn’s disease and the majority of cases were males in the adolescent or young adult age group. A few of the cases were managed with azathioprine as monotherapy, and some had been treated concurrently with a TNFa blocker prior to the diagnosis. The safety and effectiveness of azathioprine as management of Crohn’s Disease as well as ulcerative colitis are not proven.
Leukopenia, thrombocytopenia, anemias that include macrocytic anemia or pancytopenia can be observed in patients who are treated with Azathioprine. A severe bone marrow deficiency may also be observed. Hematologic toxicities are a result of dose and are more likely to be serious in patients with renal transplants who are experiencing rejection of their homograft. It is recommended that patients taking azathioprine have full blood counts, including platelet counts weekly throughout the first month and then every month for between the 2nd and 3rd month of treatment, and then every month or more often when dosage changes or other treatment changes are required. Hematologic suppression delayed may occur. Rapid reduction of dosage or temporary discontinuation of the drug could be required if there is an abrupt drop in leukocyte count or indications of bone marrow deficiency. Leukopenia is not correlated with therapeutic efficacy, so the dosage shouldn’t be increased in order to reduce the number of white blood cells.
TPMT or NUDT15 Deficiency
Patients suffering from thiopurine S-methyl Transferase (TPMT) and nucleotide diphosphatase (NUDT15) insufficient levels could be at risk of serious and potentially life-threatening myelotoxicity when receiving standard doses of azathioprine. Pancytopenia-related death has been reported in patients suffering from the absence of TPMT activity when taking azathioprine. For patients suffering from extreme
Infections that are serious
Patients taking immunosuppressants such as azathioprine are at greater risk of contracting viral, bacterial protozoal, fungal and opportunistic infections. This includes the reactivation of infections that were not present. The infections could cause serious, even death-like outcomes.
Progressive Multifocal Leukoencephalopathy
A few cases of JC virus-related infection that resulted in multifocal leukoencephalopathy that is progressive (PML) which can be tragic, are observed among patients who are treated with immunosuppressants, such as azathioprine. Factors that increase the risk of PML include the use of immunosuppressant treatments and the impairment of the immune system. Take into consideration the diagnosis of PML in any patient with new-onset neurological signs and consult neurologists as indicated by clinical evidence. Take into consideration reducing the amount of immunosuppression among patients who develop PML. For transplant patients, think about the potential risk that a reduction in immunosuppression poses to the transplant.
Effect on Sperm in Animals
Azathioprine has been found to trigger a temporary decline in spermatogenesis as well as decreases in sperm viability and number in mice given doses 10 times that of the human dose for therapeutic purposes.1 A decreased percentage of fertile matings were observed when the animals were given 5 mg/kg. 2
Pregnancy Category D.
Azathioprine tablets may cause harm to a fetus when given to pregnant women. Azathioprine tablets are not recommended to be administered to pregnant women without careful evaluation of the risk and benefits. When possible, using azathioprine tablets for pregnant women is not recommended. It should not be used in the treatment of rheumatoid arthritis during pregnant women.3
Azathioprine tablets are teratogenic for mice and rabbits when they are given in doses comparable to human dosage (5 mg/kg per day). The abnormalities include skeletal malformations as well as visceral anomalies.2
The presence of a few abnormalities, including limited immunologic function, are observed in a small number of newborns of renal allograft recipients who are taking tablets of azathioprine. In a case report that was thorough, 4 identified lymphopenia, reduced IgG as well as IgM amounts, CMV infection, and an increased thymic shadow was noticed in the infant born to a woman who received 150 mg of azathioprine and 30 mg of prednisone daily during the pregnancy. At the time of 10 weeks, all characteristics were normalized. DeWitte et al reported pancytopenia and a severe immune deficiency in the preterm infant who was fed an azathioprine dose of 125 mg and 12.5 mg of prednisone daily.5 Two reported reports of abnormal physical signs. Williamson and Karp wrote about a baby born with preaxial polydactyly, whose mother was prescribed azathioprine at 200 mg daily, and prednisone 20 mg each daily during pregnancy.6 Tallent et al described an infant that had huge myelomeningocele that was located in the upper region of the lumbar spine. bilateral dislocated hips and bilateral talipes of equinovarus. The father was receiving long-term azathioprine therapy.7
Risk versus benefit must be considered carefully prior to the use of tablets azathioprine in women with reproductive potential. There aren’t enough controlled studies on pregnant women. If this medication is used during pregnancy, or if a patient becomes pregnant while using this medication, the patient must be aware of the risk to the embryo. Women who are in the midst of becoming pregnant are advised to stay clear of becoming pregnant.
The GI hypersensitivity response that is characterized by vomiting and nausea that is severe has been documented. The symptoms can also be caused by fever, diarrhea, rash and malaise, myalgias, elevated liver enzymes, and sometimes hypotension. The symptoms of gastrointestinal toxicity typically manifest in the initial few weeks of treatment with azathioprine tablets , and are reversed after discontinuation of the medication. The reaction could be recurrent within hours following a rechallenge using a single dose of azathioprine tablets.
Information for Patients
Patients who begin taking tablets of azathioprine should be aware of the need to conduct regular blood tests while receiving the medication. They should be advised to report any abnormal bleeding or bruising to their doctor. Patients should be aware of the possibility of infections while taking tablets of azathioprine and be asked to report symptoms and signs that indicate infection to the doctor. Careful dosage instructions should be given to the patient, especially when azathioprine tablets are being administered in the presence of impaired renal function or concomitantly with allopurinol. Patients must be informed about the potential dangers associated with taking tablets of azathioprine in pregnancy as well as during the breastfeeding period. The higher likelihood of malignancy that comes with treatment using azathioprine tablets needs to be made clear to the patient.
Complete Blood Count (CBC) Monitoring
Patients taking azathioprine tablets must have full blood counts, including platelet counts every week during the first month. Then, every two months during the third and second month of treatment. Then, regularly, or more often in the event that dosage adjustments or other treatment changes are needed.
TPMT and NUDT15 Testing
Take into consideration genotyping or phenotyping patients for TPMT deficiencies and testing for NUDT15 deficiency patients suffering from severe myelosuppression. Testing for NUDT15 and TPMT cannot substitute for full blood counts (CBC) monitoring for patients taking azathioprine. The accuracy of phenotyping (red blood cell activity of TPMT) is not feasible in patients who have had the latest blood transfusions
Use in conjunction with xanthine oxidase (XO) inhibitors
One of the routes for activation of azathioprine is blocked with XO inhibitors (allopurinol or Febuxostat). Patients who are taking allopurinol and azathioprine in conjunction should receive an increase in the dose of azathioprine by approximately 1/3 to 1/4 the normal dose. Combining azathioprine and the febuxostat drug is not recommended. The inhibition of XO can increase plasma concentrations of azathioprine and its derivative 6-MP, which can cause toxic effects. It is suggested that other dosage reductions or alternative treatments be considered in patients who have insufficient or no TPMT using azathioprine as well as xanthine oxidase inhibitors, as both TPMT and XO activation processes can be in a state of disruption
Use in conjunction with the drug ribavirin
Ribavirin’s use for hepatitis C in patients who are receiving Azathioprine has been shown to trigger severe pancytopenia and could raise the chance of myelotoxicity related to azathioprine. Inosine monophosphate dehydrogenase (IMDH) is essential to regulate an important metabolic pathway used by azathioprine. Ribavirin has been proven to block IMDH which leads to the formation of an azathioprine-derived metabolism product, 6-methylthioionosine monphosphate (6MTITP) which is linked with myelotoxicity (neutropenia and thrombocytopenia as well as anemia). Patients taking azathioprine in combination with ribavirin must be able to have complete blood counts including platelet counts being monitored every week for the first month, then every two months during the second as well as the third month of therapy, and finally every month or more often in the event that dosage or therapy modifications are needed.
Tablets containing azathioprine for pregnant mothers are not advised. Azathioprine and its derivatives can be transported at low levels both transplacentally and within breast milk.8 9, 10, Due to the possibility of the development of tumours that have been observed for azathioprine It is imperative that a choice be taken whether to cease nursing or stop taking the medication considering the significance of the drug for the mother.
The safety and effectiveness of azathioprine for pediatric patients has not been proven.
The main and potentially harmful adverse side effects of the tablets of azathioprine include digestive and hematologic. The dangers of secondary infection, as well as malignancy, are significant. The incidence and severity of adverse reactions rely on the dosage and time of azathioprine tablets in addition to the patient’s condition or other treatments. The risk of hematologic toxicities as well as Neoplasia that is seen in the groups consisting of recipients from renal homografts is considerably more frequent than those in studies using tablets containing azathioprine to treat rheumatoid.
Leukopenia and/or thrombocytopenia can be dose-dependent and may develop late in the course of treatment using tablets of azathioprine. Reduction in dose or temporary withdrawal could cause a reversal of these adverse reactions. Infection can be an outcome of leukopenia or bone marrow suppression However, the rate of infection during renal homotransplantation ranges from 30-60 times greater than in rheumatoid arthritis. Anemias, such as bleeding or macrocytic anemia, have been reported.
Vomiting and nausea can occur in the initial few months of treatment with tablets of azathioprine and was observed in about 12percent of 676 patients suffering from rheumatoid arthritis. It is possible that the frequency and severity of stomach disorders typically decrease with taking the medication in small doses, and/or following meals. In some patients, nausea and vomiting could be very severe and can be accompanied by signs like fever, diarrhea or malaise. The vomiting that causes abdominal pain can be rare in the case of pancreatitis with a hypersensitivity. Hepatotoxicity manifested by an increase in the serum alkaline phosphatase, or transaminases, is thought to happen following the use of azathioprine mostly for allograft recipients. Hepatotoxicity is rare (less than 1percent) in patients with rheumatoid arthritis. Hepatotoxicity that occurs after transplantation usually occurs within six months of transplantation and can be reversed when azathioprine tablets are stopped. Rare, but potentially life-threatening hepatic veno-occlusive illness that occurs with the long-term use of azathioprine has been observed in transplant patients and one patient who received tablets of azathioprine for panuveitis.11 13 A periodic measurement of alkaline phosphatase, serum transaminases and bilirubin are recommended for the early detection of hepatotoxicity. If the hepatic-related veno-occlusive disease is suspect in clinical terms, the azathioprine tablet should be removed permanently.
Additional adverse effects that are low frequency have been documented. This includes skin rashes the alopecia, fevers and arthralgias. They also report diarrhea, Steatorrhea, Negative nitrogen balance and reversible interstitial pneumonia and hepatosplenic lymphoma (
The oral LD50s for one tablet of azathioprine for rats and mice is 2500 mg/kg and 300 mg/kg, respectively. Massive dosages of the antimetabolite could result in marrow hypoplasia infected bleeding or death. Around 70% of azathioprine is bound to serum proteins however approximately 45% of it is removed in an 8-hour hemodialysis.14 A single instance was reported of a patient undergoing a kidney transplant who consumed an entire amount of 7500 mg of azathioprine. The first toxic reaction was nausea vomiting, diarrhea, and nausea which were then mild leukopenia, and minor liver dysfunctional issues. The white blood cells count, SGOT and bilirubin were back to normal within 6 days of the overdose.
DOSAGE AND ADMINISTRATION
The dosage of tablets containing azathioprine needed to avoid rejection and limit toxicity could differ for each patient; this requires careful monitoring. The dose that is recommended for initial use is typically between 3 and 5 mg per day starting at the time of the transplant. Azathioprine tablets are typically taken as a daily dose during the day prior to or in a few of instances, 1 to 3 days prior to, the transplant. A dose reduction to maintenance doses of 1 to 3 mg/kg is generally feasible. The dosage of azathioprine tablets is not to be increased beyond toxic levels due to the risk of rejection. The discontinuation of treatment is sometimes necessary in cases of serious hematologic or other toxicities and rejection to the homograft could be the result of the withdrawal of the drug.
Azathioprine tablets are generally taken on a regular basis. The dose for initial dosage should be around 1.0 mg/kg (50 to 100 mg) administered as one dose or as part of a daily basis on a two-day schedule. The dosage can be increased from 6-8 weeks, and afterwards in steps of 4 weeks intervals in the event of no significant toxicities or if your initial response is not satisfactory. Dose increments must be 0.5 mg/kg per day, until a maximum dosage of 2.5 mg/kg/day. The therapeutic response can be observed after a few weeks of treatment generally 6 to 8 An adequate trial must be at a minimum of 12 weeks. Patients who are not improving after 12 weeks are classified as refractory. Azathioprine tablets are able to be taken long-term for patients with a clinical improvement, however, patients should be watched closely and a gradual reduction in dosage should be considered to lower the chance of adverse reactions.
Maintain therapy is recommended to be administered at the lowest dose effective and the dosage can be reduced gradually by adjusting it to 0.5 mg/kg or 25 mg per day every four weeks while other therapies are maintained at the same level. The ideal duration for maintenance tablets of azathioprine is not yet known. Azathioprine tablets can be removed abruptly, however, delayed effects could occur.
Patients suffering from TPMT or NUDT15 Deficiency
Examine the possibility of TPMT and NUDT15 deficiency among patients suffering from severe bone marrow reactions. The possibility of early drug discontinuation is contemplated in patients who have unusual CBC results that fail to respond to reduction of dose
Use in Renal Dysfunction
Patients with a relative oliguric condition, particularly those who suffer from tubular necrosis within the immediate post cadaveric post-transplant period could experience delayed clearance of tablets containing azathioprine or its metabolites. They could be especially susceptible to this drug and typically are prescribed smaller doses.
The proper disposal and handling of this antimetabolite medication that is immunosuppressive must be taken into consideration. A number of guidelines related to this topic were published.15-21 There isn’t a general agreement on whether all of the methods suggested within the guidance are needed or suitable.