Date of approval.
Date of revision.
Azathioprine Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
[Drug Name] Generic Name: Azathioprine TabletsEnglish Name: Azathioprine TabletsHanyu Pinyin: Liuzuopiaoling Pian
Ingredients
The main ingredient of this product is azathioprine.
Chemical name: 6-[5-(1-methyl-4-nitro-1H-imidazolyl)thio]-1H-purine. Chemical structure formula.
Molecular formula: C9H7N7O2S
Molecular weight: 277.27
Excipients: lactose, stearic acid, pregelatinized starch, anhydrous lactose, corn starch, magnesium stearate and film-coated premix (gastric soluble type). Characteristic】
This product is film-coated tablets, light yellow after removing the coating. Indications
It can be used in combination with corticosteroids and/or other immunosuppressive agents and therapeutic measures to prevent rejection in patients with organ transplantation (kidney transplantation, heart transplantation and liver transplantation). It can also reduce the need for corticosteroids in renal transplant patients.
It is usually used in combination with corticosteroids and/or other immunosuppressive agents and therapies or alone to achieve clinical efficacy (including corticosteroid tapering) in the following patients
Severe rheumatoid arthritis.
Systemic lupus erythematosus.
Dermatomyositis.
Autoimmune chronic active hepatitis.
Polyarteritis nodosa.
Autoimmune hemolytic anemia.
Spontaneous thrombocytopenic purpura; [Specification
50mg [dosage].
This product must be swallowed with sufficient amount of water after meals.
After organ transplantation, treatment should be maintained for a long time, otherwise the expected rejection will occur.
Patients should follow the treatment regimen reliably and systematically during either acute or long-term treatment so that successful results may be achieved.
When using this product in special cases, please refer to prior expert advice.
Dosage for organ transplantation – adults and children.
First day dose.
The dose of this product depends on the immunotherapy regimen used, usually the first day dose is up to a maximum of 5 mg per kg body weight per day.
Maintenance dose.
The maintenance dose is adjusted according to clinical need and hematologic tolerance and is usually 1 to 4 mg per kg of body weight per day.
Therapeutic Doses for Other Diseases – Adults and Children.
In general, the starting dose of this product is 1 to 3 mg/kg/day and is adjusted accordingly within this range during continuous treatment, depending on the clinical response (which may not occur for months or weeks) and the tolerance of the hematologic system.
When therapeutic effects are evident, a reduction in dosing to the lowest dose that maintains efficacy should be considered as a maintenance dose. If there is no improvement within 3 months, discontinuation of the product should be considered. The maintenance dose of this product ranges from less than 1 mg per kg body weight per day to 3 mg per kg body weight per day, depending on the need for clinical treatment and the individual patient’s response, including hematologic tolerability.
In patients with hepatic and/or renal insufficiency, the lower limit of the recommended dose range should be used. (See [Precautions])
This product should never be broken or fragmented and should not be accepted in a broken outer package; hand-held with the film coating intact is not harmful and no additional protective measures are required.
Or follow medical advice. Adverse reactions
According to foreign literature reports.
Summary of safety characteristics
For this product, there is no modern clinical documentation that can be used to determine the frequency of adverse reactions. The incidence of adverse reactions varies depending on the indication. The following conventions are used for frequency classification.
The following conventions were used to classify frequency: very common (≥1/10), common (≥1/100 and <1/10), occasional (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), and very rare (<1/10,000).
Systemic Organ Classification Frequency Adverse Reactions Infectious and Infectious Diseases Very Common This product in combination with other immunosuppressive agents for transplant patients: viral, fungal and bacterial infections Occasionally in other patient populations: viral, fungal and bacterial infections Very Rare This product in combination with other immunosuppressive agents: JC virus-associated PML cases (see [Precautions]) Benign, malignant tumors (including cysts and polyps) Rare Various tumors, including lymphoproliferative disorders, skin cancers (melanoma and non-melanoma), sarcomas (Kaposi’s sarcoma and non-Kaposi’s sarcoma), and cervical cancer in situ, acute myelogenous leukemia and myelodysplasia (See [Precautions]) Very rare hepatosplenic T-cell lymphoma (See [Precautions]) Blood and lymphatic system disorders Very common leukopenia Common thrombocytopenia Occasional anemia Rare granulocyte deficiency, pancytopenia, aplastic anemia, megaloblastic anemia, bone marrow failure Immune system disorders Occasional hypersensitivity reactions Very rare Stevens -Johnson syndrome, toxic epidermolysis bullosa respiratory, thoracic and mediastinal disorders very rare reversible pneumonia gastrointestinal disorders common nausea occasional pancreatitis very rare transplant population.
Colitis, diverticulitis and intestinal perforation.
Inflammatory bowel disease population: severe diarrhea hepatobiliary system disease occasional cholestasis rare life-threatening liver injury skin and subcutaneous tissue disorders rare alopecia unknown acute febrile neutrophilic dermatosis (Sweet’s syndrome), photosensitivity reactions various tests occasional abnormal liver function tests
Description of selected adverse reactions
Infectious and Infectious Diseases.
Increased susceptibility to viral, fungal and bacterial infections (including severe or atypical infections) and reactivation of VZV, hepatitis B and other infectious agents in patients receiving azathioprine monotherapy or in combination with other immunosuppressive agents (especially corticosteroids).
Carcinogenicity (see [Precautions]).
Benign and malignant tumors (including cysts and polyps).
Rare: Neoplasms, including non-Hodgkin’s lymphoma and other malignancies, especially skin cancer (melanoma and non-melanoma), sarcomas (Kaposi’s sarcoma and non-Kaposi’s sarcoma), and cervical cancer in situ, acute myelogenous leukemia and myelodysplasia. (See [Precautions])
Patients receiving immunosuppression have an increased risk of developing non-Hodgkin’s lymphoma and other malignancies, particularly skin cancers (melanoma and non-melanoma), sarcomas (Kaposi’s sarcoma and non-Kaposi’s sarcoma), and cervical cancer in situ, especially in transplant patients receiving shock therapy, which should be maintained at the lowest effective dose level. Immunosuppressed patients with rheumatoid arthritis have an increased risk of non-Hodgkin’s lymphoma compared to the general population and appear to be at least partially related to the disease itself.
Acute myelogenous leukemia and myelodysplasia (partly associated with chromosomal abnormalities) have been reported rarely.
Blood and lymphatic system disorders.
This product may be associated with a suppressive effect on bone marrow function that is dose-related and usually reversible. Most commonly, leukopenia, sometimes anemia and thrombocytopenia, and rarely granulocyte deficiency, allohemocytopenia, and aplastic anemia occur. Most of these conditions occur in patients with a predisposition to myelotoxicity, such as TPMP deficiency, hepatic and renal dysfunction, and in patients receiving concomitant allopurinol therapy who have failed to reduce the dose of this product. (See [Drug Interactions])
An increase in mean erythrocyte volume and erythrocyte hemoglobin volume associated with treatment with this drug is reversible in a dose-dependent manner. Megaloblastic bone marrow alterations have also been observed, but severe megaloblastic anemia and erythrocyte dysplasia are rare.
Immune system disorders.
Very rare: Stevens-Johnson Syndrome and toxic epidermolysis bullosa.
Several allergic reactions may be observed clinically, mainly in the form of general malaise, dizziness, nausea, vomiting, diarrhea, fever, chills, rash, rash, vasculitis, myalgia, arthralgia, hypotension, hepatic and renal dysfunction, and biliary depression (see Gastrointestinal Reactions section).
In most cases, repeated dosing proved adverse reactions associated with this product.
Most adverse reactions resolve with immediate discontinuation of azathioprine and administration of appropriate supportive circulatory therapy.
Very few cases have been reported with apparent lesions leading to death.
The need to continue treatment with Azathioprine should be carefully considered on a patient-by-patient basis following an allergic reaction to the drug.
Respiratory, thoracic and mediastinal disorders.
Reports of reversible pneumonia are extremely rare.
Gastrointestinal Disorders.
A small number of patients experienced nausea after the first dose of this product, which was relieved by postprandial dosing.
Serious complications such as colitis, diverticulitis, and intestinal perforation have been reported in organ transplant patients receiving immunosuppressive therapy, but the etiology is still not established and does not exclude the association of this reaction with the use of high doses of corticosteroids. It has been reported that the use of this product in patients with enterocolitis can lead to severe diarrhea, which is repeated after repeated dosing. When this product is used in such patients, it should be kept in mind that the deterioration may be drug-related.
Pancreatitis has been reported in a few patients treated with this product, especially in renal transplant patients who have been diagnosed with enterocolitis. It is difficult to establish that pancreatitis is related to the use of a particular drug, although reoccurrence of the reaction has been confirmed in individual cases with repeated dosing.
Hepatobiliary system disorders.
Biliary depression and hepatic failure have occasionally been reported with treatment with this product and usually recovered with discontinuation of the drug. These conditions may be associated with signs and symptoms of allergic reactions (see Immune System Disorders).
Rare, fatal liver damage has been associated with long-term azathioprine administration, primarily in organ transplant patients. Histologic examination includes sinusoidal gap dilatation, purpuric hepatitis, veno-occlusive disease, and small nodal regenerative hyperplasia. Short- or long-term hepatic histology, signs and symptoms may be obtained in some cases after discontinuation of azathioprine.
Skin and subcutaneous tissue disorders.
Alopecia occurs in individual patients due to concomitant administration of azathioprine and other immunosuppressive drugs; in most cases it resolves spontaneously without discontinuation, so it is uncertain whether alopecia is associated with azathioprine therapy.
Susceptibility.
Patients receiving this product alone or in combination with other immunosuppressive agents, particularly corticosteroid preparations, have increased susceptibility to viral, fungal, and bacterial infections.
Case reports of JC virus associated with progressive multifocal leukoencephalopathy following co-administration of azathioprine with other immunosuppressive agents are rare. (See [Precautions])
Two adverse events, allergic asthma and hand tremor, were reported during the use of this product from January 1, 1999, to May 19, 2004, and were judged to be possibly related to the administration of the drug.
[Contraindication].
Contraindicated in persons with a history of hypersensitivity to azathioprine or any other component.
Hypersensitivity to 6-mercaptopurine (6-MP) is also possible. Precautions
According to foreign literature.
Dosage monitoring
The use of this product is potentially hazardous and should only be administered if adequate monitoring of adverse reactions is ensured throughout the treatment period.
Complete blood counts, including platelets, should be performed at least weekly for the first 8 weeks of treatment; the frequency of complete blood counts should be increased if high doses are administered or if the patient has hepatic and/or renal insufficiency. Thereafter, the frequency of tests may be reduced, but it is still recommended that they be performed monthly, or at least every three months.
Patients receiving this product should be advised to notify their physician immediately of any infection, accidental injury, bleeding, or other manifestation of bone marrow suppression.
Renal and/or Hepatic Insufficiency
Patients with hepatic or renal insufficiency should be monitored with special attention to the hematologic system and the dose should be reduced.
The toxicity of this product may be enhanced with renal insufficiency, but has not been confirmed by the results of controlled studies. Nevertheless, administration at the lower limit of normal dosing is recommended and the hematologic response should be closely monitored and the drug dose further reduced if hematologic toxicity occurs. Treatment should be interrupted immediately upon initial abnormal decreases in blood counts, as leukocyte and platelet decreases may continue after discontinuation of treatment.
Care should also be taken when administering this product to patients with hepatic impairment, with regular checks of complete blood counts and liver function. Because the metabolism of this product may be affected in such patients, this product should be administered at the lower limit of the recommended dose. When hepatic or hematologic toxicity occurs, the drug dose should be further reduced. More frequent monitoring is recommended for patients with pre-existing liver disease or who are being treated for other potential hepatotoxicity. If significant jaundice develops, patients should be advised to discontinue azathioprine immediately.
Tired-Nyhan syndrome (Lesch-Nyhan syndrome)
There is limited evidence that the use of this product is detrimental to patients with hypoxanthine-guanine-phosphate ribosyltransferase deficiency (Lesch-Nyhan syndrome); therefore, it should not be used in patients with such metabolic disorders.
Use with caution in patients receiving concurrent or recently completed cell growth inhibitor/myelosuppressive therapy. (See [Drug Interactions])
Immunization with live biological vaccines has the potential to cause infection in immunocompromised hosts; live vaccines are contraindicated in patients receiving this product and patients are advised to wait at least 3 months after the end of azathioprine therapy before receiving live bacterial vaccines. (See [Drug Interactions])
The combination of ribavirin and azathioprine is not recommended. Ribavirin may reduce the efficacy and increase the toxicity of azathioprine. (See [Drug Interactions])
Thiopurine methyltransferase (TPMT)
Individuals with hereditary thiopurine methyltransferase (TPMT) deficiency may be unusually sensitive to the myelosuppressive effects of azathioprine and have a tendency to develop rapid myelosuppression during the initial period of treatment with azathioprine, which is exacerbated by the combination of TPMT inhibitors such as olsalazine, mesalazine, or salazosulfapyridine. A possible association between reduced TPMT activity and secondary leukemia and myelodysplasia has been reported in patients treated with 6-mercaptopurine (the active metabolite of azathioprine) in combination with other cytotoxic drugs (see [Adverse Reactions]). Some laboratories offer tests for TPMT deficiency, although these tests are not yet able to detect all patients at risk of serious toxicity. Therefore, close monitoring of blood counts is still required. Dose reductions of azathioprine may be required when azathioprine is used in combination with other drugs whose primary or secondary toxicity is bone marrow suppression. (See [Drug Interactions])
NUDT15 mutation
Patients with inherited mutations in the NUDT15 gene are at increased risk of severe mercaptopurine toxicity, such as early leukopenia and alopecia, with conventional doses of mercaptopurine therapy, often requiring significant dose reductions. Patients of Asian descent are at particularly high risk due to the increased frequency of mutations in Asian ethnic groups. The optimal starting dose for patients with heterozygous or pure-hybrid defects has not been determined. Genotypic and phenotypic testing for the NUDT15 variant should be considered before starting mercaptopurine therapy in all patients, including pediatric patients, to reduce the risk of severe leukopenia and alopecia associated with mercaptopurine, especially in Asian populations.
Hypersensitivity reactions
Patients with suspected prior hypersensitivity reactions to 6-mercaptopurine are not recommended for their prodrug azathioprine and vice versa, unless the patient’s hypersensitivity to one drug is confirmed by allergy testing and the test is negative for the other drug.
Mutagenicity
Chromosomal abnormalities have been confirmed in both male and female patients treated with azathioprine. It is difficult to assess the role of azathioprine in these abnormalities.
Chromosomal abnormalities have been shown to disappear over time in lymphocytes from the offspring of patients treated with azathioprine. With the exception of very few cases, no physical evidence of significant abnormalities has been observed in the offspring of patients treated with azathioprine.
Azathioprine and long-wave ultraviolet light have been shown to have a synergistic chromosomogenic breakage effect in patients treated with azathioprine for a variety of diseases.
Effects on fertility
The specific effects of azathioprine treatment on human fertility are not known, but there are reports that children can be born after treatment. Several studies have reported that standard doses of azathioprine do not appear to affect male fertility.
In both male and female transplant recipients, fertility improved as chronic renal insufficiency remitted after treatment with azathioprine for kidney transplantation.
As with all cytotoxic chemotherapeutic agents, spouses of patients treated with this product need to use adequate contraception.
Carcinogenicity
Patients receiving immunosuppressive therapy have an increased risk of developing non-Hodgkin’s lymphoma and other malignancies, particularly skin cancer (melanoma and non-melanoma), sarcoma (Kaposi’s sarcoma and non-Kaposi’s sarcoma), and cervical cancer in situ, which appears to be related to the intensity and duration of immunosuppression received and not to the type of drug used. It has been reported that reduction or discontinuation of immunosuppression may be associated with partial or complete regression of non-Hodgkin’s lymphoma and Kaposi’s sarcoma.
Regimens containing multiple immunosuppressive agents, including mercaptopurine, should be used with caution, as this may lead to lymphoproliferative disorders, some of which have been reported to be fatal. Concomitant administration of multiple immunosuppressive agents can increase the risk of EBV (Epstein-Barr virus)-associated lymphoproliferative disorders.
Hepatosplenic T-cell lymphoma has been reported when azathioprine is administered alone or in combination with anti-TNF agents or other immunosuppressive agents. Although most reported cases occur in the inflammatory bowel disease (IBD) population, cases have been reported outside of this population.
Patients treated with multiple immunosuppressive agents are at risk of immune oversuppression, so this treatment should be maintained at the lowest effective dose level. Patients at increased risk for skin cancer should minimize exposure to sunlight and UV rays by using protective clothing and using sunscreens with a high protection factor. (See [Adverse Reactions])
Macrophage activation syndrome
Macrophage activation syndrome (MAS) is a known life-threatening condition that can occur in patients with autoimmune diseases, particularly IBD, and the use of azathioprine may increase susceptibility to the condition. If MAS occurs or is suspected, evaluation and treatment should be started as soon as possible and azathioprine therapy should be discontinued. Physicians should be aware of symptoms of infections, such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.
Varicella zoster virus infection
Varicella zoster virus (VZV; varicella and herpes zoster) infections may become severe during the use of immunosuppressive drugs. Special attention should be paid to the following.
The prescriber should check the patient for a history of VZV before starting immunosuppressant administration. Serologic testing can be used to determine prior exposure. Patients with no history of exposure should avoid contact with patients with varicella or herpes zoster. If a patient has been exposed to VZV, special care must be taken to avoid the patient developing varicella or herpes zoster, and passive immunization with varicella-zoster immunoglobulin (VZIG) should be considered.
If a patient is infected with VZV, appropriate measures should be taken, including antiviral therapy and supportive treatment. (See [Adverse Reactions])
Progressive multifocal leukoencephalopathy (PML)
Progressive multifocal leukoencephalopathy, an opportunistic infection caused by JC virus, a type of human polyomavirus, has been reported in patients who were given azathioprine in combination with other immunosuppressive drugs. Immunosuppressive therapy should be discontinued at the initial appearance of signs or symptoms of PML, and appropriate evaluation and diagnosis should be made. (See [Adverse Reactions])
Hepatitis B
Patients receiving immunosuppressive therapy who are hepatitis B virus carriers (defined as patients who have been positive for hepatitis B surface antigen [HBsAg] for more than 6 months) or who have documented prior HBV infection are at risk of HBV replication reactivation with asymptomatic elevation of serum HBV DNA and ALT levels. Treatment, including prophylaxis with oral anti-HBV drugs, may be considered in accordance with local guidelines. (See [Adverse Reactions])
Xanthine oxidase inhibitors
If allopurinol, oxopurinol, and/or thiopurinol are administered concomitantly with azathioprine, the dose of azathioprine must be reduced to one-fourth of the original dose.
Neuromuscular drugs
Special caution is required when azathioprine is administered concomitantly with neuromuscular acting drugs such as cartridge toxin or succinylcholine. It can also potentiate neuromuscular blockade produced by depolarizing agents such as succinylcholine. It is recommended that patients treated with azathioprine should proactively inform their anesthesiologist prior to surgery. (See [Drug Interactions])
Pregnant women and nursing mothers
Pregnant women
This product is contraindicated in pregnant women or women who are planning to become pregnant in the near future.
This product has potential teratogenic effects in humans. Therefore, spouses of patients treated with this product should be advised to use adequate contraception. If the patient becomes pregnant, the advantages and disadvantages should be carefully weighed. Because teratogenicity has been observed in animal studies. (See [Pharmacology and Toxicology])
Low concentrations of azathioprine and/or its metabolites have been measured in fetal blood and amniotic fluid following administration of azathioprine to pregnant women.
There have been reports of leukopenia and/or thrombocytopenia in newborns born to some pregnant women who have taken azathioprine during pregnancy, so additional hematologic monitoring is recommended for patients taking azathioprine during pregnancy.
Lactating Women
6-Mercaptopurine (an azathioprine metabolite) has been shown to be measured in colostrum and breast milk in lactating women taking azathioprine. Therefore, patients taking this product should not breastfeed. For children
See [Dosage and Administration] section or as directed by your physician. Geriatric use
There is limited experience with this product in the elderly and although the available data do not demonstrate a higher incidence of side effects in the elderly, the lower limit of the recommended dose range is recommended.
The hematologic parameters of the elderly should be paid extra attention to and the lowest clinically effective dose should be used as the maintenance dose. Drug Interactions]
According to foreign literature.
Allopurinol.
Allopurinol inhibits xanthine oxidase, which leads to the conversion of biologically active 6-thioguanosine to inactive 6-thioureido acid. When allopurinol, oxopurinol, and/or thiopurinol are combined with 6-mercaptopurine or azathioprine, the dose of azathioprine should be reduced to one-fourth of the original dose.
Other xanthine oxidase inhibitors, such as febuxostat, may decrease the metabolism of this product. Combination dosing is not recommended because the data are insufficient to determine an appropriate dose reduction.
Neuromuscular blocking agents.
This product may potentiate the neuromuscular blocking effects of depolarizing drugs such as: succinylcholine, as well as attenuate the neuromuscular blocking effects of non-depolarizing drugs such as: cylindrotoxin, arrowroot and pancuronium bromide. Experimental data confirm that azathioprine reverses the neuromuscular blockade produced by d-tubercurarotoxine. (See [Caution])
Anticoagulants.
This product may cause a reduction in the anticoagulant effect of warfarin. The anticoagulant effect of vinblastine has been reported to be inhibited when co-administered with azathioprine; therefore, higher doses of anticoagulants may be required. Close monitoring of coagulation is recommended when anticoagulants are administered concomitantly with azathioprine.
Cell growth inhibitors/myelosuppressants.
Combination with cell growth inhibitors and bone marrow inhibitors, e.g., penicillamine, should be avoided whenever possible during treatment with this product. There have been conflicting clinical reports of serious hematologic abnormalities associated with the combination of this product and methotrexate/sulfamethoxazole (cotrimoxazole).
One case report suggested the possibility of hematologic abnormalities with the combination of this product and the angiotensinase inhibitor captopril.
This product has the potential to potentiate the myelosuppressive effects of cimetidine and indomethacin.
Ribavirin.
Ribavirin inhibits inosine monophosphate dehydrogenase (IMPDH), resulting in decreased production of active 6-thioguanine nucleotides. Severe myelosuppression has been reported following co-administration of azathioprine and ribavirin; therefore, combined administration is not recommended. (See [Precautions])
Methotrexate.
Methotrexate (20 mg/m2 orally) increased the AUC of 6-mercaptopurine by approximately 31%, and methotrexate (2 or 5 g/m2 intravenously) increased the AUC of 6-mercaptopurine by 69% and 93%, respectively. Therefore, when azathioprine is administered concomitantly with high-dose methotrexate, the dose should be adjusted to maintain an appropriate white blood cell count.
Infliximab.
Interactions between azathioprine and infliximab have been observed. Patients being treated with azathioprine experienced a transient increase in 6-TGN (6-thioguanine nucleotide, the active metabolite of azathioprine) levels and a decrease in mean white blood cell count in the first few weeks following infusion of infliximab, returning to previous levels after 3 months.
Other interactions.
TPMT-deficient patients.
Because of in vitro test evidence of inhibitory effects of aminosalicylic acid derivatives (olsalazine, mesalazine, and salazosulfapyridine) on TPMT, caution should be exercised when patients are being treated with this drug.
Patients with minimal or no hereditary thiopurine methyltransferase (TPMT) activity have an increased risk of severe azathioprine toxicity from conventional doses of azathioprine and usually require significant dose reductions. The optimal starting dose for patients with pure heterozygous deficiencies has not been determined.
Most patients with heterozygous TPMT deficiency can tolerate the recommended dose of azathioprine, but some patients may require a lower dose. genotypic and phenotypic testing for TPMT is available. (See [Caution])
Patients with NUDT15 variants.
Patients with inherited NUDT15 mutations are at increased risk of severe mercaptopurine toxicity, such as early leukopenia and alopecia, with conventional doses of mercaptopurine therapy and usually require significant dose reductions. Patients of Asian descent are at particularly high risk due to the increased frequency of mutations in Asian ethnic groups. The optimal starting dose for patients with heterozygous or pure-hybrid defects has not been determined.
Genotypic and phenotypic testing for the NUDT15 variant should be considered before starting mercaptopurine therapy in all patients, including pediatric patients, to reduce the risk of severe leukopenia and alopecia associated with mercaptopurine, particularly in Asian populations.
Vaccine.
The immunosuppressive activity of this product is capable of causing an atypical potential for damage to live vaccines. Therefore, the use of live vaccines in patients treated with this product is theoretically contraindicated and patients are advised to wait at least three months after the end of azathioprine therapy before receiving live vaccines. (See [Precautions])
This product is likely to have an attenuating effect on inactivated vaccine, and such effects have been reported after administration of hepatitis B vaccine in patients on a combination of azathioprine and corticosteroids.
A small clinical study showed no effect on the activity of polyvalent pneumococcal vaccine, as evaluated by the mean concentration of anti-membrane specific antibodies. [Drug Overdose].
Signs and Symptoms.
Signs after overdose of this product mainly include infection of unknown cause, laryngeal ulceration, purpura and bleeding, caused by maximum bone marrow suppression after 9 to 14 days of dosing. This sign is more likely to occur in chronic overdose than in a single overdose. There is a report of a patient who, after a single ingestion of 7.5 g of this product, began with toxic reactions of nausea, vomiting and diarrhea, followed by moderate leukopenia and mild abnormalities of liver function, followed by a smooth return to normal.
Treatment.
No specific antidote is available. In case of overdose, gastric lavage and clinical monitoring, including hematology, are indicated, and prompt management of all possible further adverse reactions is mandatory. Although azathioprine can be partially dialyzed, the effectiveness of dialysis in patients with overdose remains unclear. Pharmacology and Toxicology]
Pharmacodynamics
Azathioprine is an imidazole derivative of 6-mercaptopurine. Until the detailed mechanism of action is elucidated, several possible mechanisms of action are described as follows.
(l) The released 6-mercaptopurine is an antagonist of purine metabolism.
2) The effect of alkylation on the closure of the functional group-mercapto group.
3) Inhibition of nucleic acid biosynthesis through multiple pathways, thereby preventing the proliferation of cells involved in immune recognition and immune amplification.
4) Incorporation of thiopurine analogues into the deoxyribonucleic acid (DNA) chain, which leads to DNA destruction.
Based on the above mechanism of action, the product is effective only after weeks or months of treatment with the drug.
Preclinical Safety
Mutagenicity.
Chromosomal abnormalities have been shown to occur in both male and female patients treated with this drug. Reversible chromosomal mutations have occurred in the next generation of patients treated with this drug. With the exception of a few rare cases, no evidence of significant physical abnormalities has been observed in these children. Azathioprine and long-wave ultraviolet light produce synergistic teratogenic effects.
Teratogenicity.
Studies in pregnant rats and rabbits have shown that azathioprine administered at 5-15 mg/kg bw/day during the organogenesis period causes varying degrees of fetal abnormalities. Pregnant rabbits administered at a dose of l0 mg/kg bw/day produced significant teratogenicity. The teratogenic effect of this product in humans has not been determined. (See [Precautions] for contraceptive measures)
Carcinogenicity.
Shock therapy in transplant patients can increase the risk of post-transplant lymphoma, so the drug should be adjusted to the lowest effective dose. The increased risk of lymphoma in patients with immunosuppressed rheumatoid arthritis is at least partially related to the disease itself. The higher incidence of skin cancer in transplant patients than in the general population may be partly related to immunosuppressive therapy. [Pharmacokinetics].
Azathioprine is well absorbed in the gastrointestinal tract.
Plasma radioactivity peaks in 1 to 2 hours and has a half-life of 4 to 6 hours as measured by the isotope 35S-azathioprine. Although this half-life value is not an actual value for azathioprine, it reflects the plasma elimination of azathioprine and 35S-binding metabolites. Because azathioprine rapidly produces a large series of metabolites, only a portion of the plasma drug concentration as determined by radioactivity is the drug prototype. The mean plasma half-life of azathioprine after intravenous administration ranged from 6 to 28 minutes; the mean plasma half-life of 6-mercaptopurine ranged from 38 to 114 minutes.
Studies in mice given the isotope 35S -thiazathioprine showed no abnormally high concentrations of azathioprine in all tissues, but very small amounts of 35S were measured in the brain. azathioprine rapidly breaks down in vivo to 6-mercaptopurine and methylnitroimidazole. 6-mercaptopurine rapidly crosses cell membranes and is converted intracellularly into a large number of purine analogues, of which the major active substances are Thioglycosides, the rate of conversion varies according to individual differences. Since nucleosides cannot cross cell membranes and thus cannot enter the humoral circulation, 6-mercaptopurine, whether used directly or converted in vivo from azathioprine, is eliminated primarily by metabolism to the inactive oxidized metabolite 6-thioureido acid. This oxidation is catalyzed by xanthine oxidase, which can be blocked by allopurinol.
The role of the breakage product methylnitroimidazole has been described in detail. In some systems, it can exhibit altered activity of azathioprine compared to 6-mercaptopurine. Plasma levels of azathioprine and 6-mercaptopurine have not been found to correlate with the therapeutic effects and toxic effects of this product. Azathioprine is excreted in the urine mainly as 6-thiourea acid, with a small amount of 1-methyl-4-nitro-5-thiimidazole in the urine. This phenomenon suggests that azathioprine is not only metabolized by nucleophilic reagents attacking the 5-position of the nitroimidazole ring and breaking it to produce 6-mercaptopurine and 1-methyl-4-nitro-5-(thioglutaryl)-imidazole, but also that only a small amount of azathioprine is excreted in the urine as a prototype Storage Storage】Store under shade and seal. Package】Packaged in aluminum-plastic blister. 25 tablets/plate, 1 plate/box; 2 plates/box; 4 plates/box. Expiration date】18 months.
【Execution Standard】.
【Approval Number】State Drug Certificate H33020153
[Drug marketing license holder
Name: Zhejiang Otocon Pharmaceutical Group Co.
Registered address: Dingye New Village, Wucheng District, Jinhua City, Zhejiang Province [Manufacturer
Company name: Zhejiang Otocon Pharmaceutical Group Co.
Production Address: Dingye New Village, Wucheng District, Jinhua City, Zhejiang Province
Postal code: 321053
Telephone number: 0579-82020725 0579-82020137
Fax number: 0579-82020725
Web
Address: http://www.zjatk.com