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Azacitidine | CAS No: 320-67-2 | GMP-certified suppliers
A medication that treats various myelodysplastic syndromes, acute myeloid leukemia, and juvenile myelomonocytic leukemia by targeting malignant hematopoietic cells to improve patient outcomes.
Therapeutic categories
Primary indications
- Azacitidine (for subcutaneous or intravenous use) is indicated for the treatment of adult patients with the following French-American-British (FAB) myelodysplastic syndrome (MDS) subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL)
- Azacitidine is also indicated for the treatment of pediatric patients aged 1 month and older with newly diagnosed Juvenile Myelomonocytic Leukemia (JMML)
- Azacitidine (for oral use) is indicated for continued treatment of adult patients with acute myeloid leukemia (AML) who achieved first complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy
Product Snapshot
- Azacitidine is available as injectable powders for intravenous or subcutaneous administration and oral tablets
- It is primarily used for treating specific subtypes of myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), and for maintenance therapy in acute myeloid leukemia (AML)
- The product is approved for use in key regulatory markets including the US, EU, and Canada
Clinical Overview
Azacitidine exerts its pharmacological effects through two main mechanisms. As an analogue of cytidine, it incorporates into RNA and DNA, disrupting RNA metabolism, inhibiting protein synthesis, and inducing cytotoxicity. It also acts as an inhibitor of DNA methyltransferase, leading to hypomethylation of DNA. This hypomethylation is thought to restore normal gene function, especially those involved in cellular differentiation and proliferation. These combined actions result in selective cytotoxicity predominantly in rapidly dividing hematopoietic cells characteristic of the malignancies treated.
After cellular uptake, azacitidine undergoes phosphorylation to active nucleotide forms that incorporate into nucleic acids. It disrupts RNA structure and function and inhibits DNA methylation by covalent binding to DNA methyltransferases. This dual mechanism causes apoptosis of malignant cells while sparing non-proliferating cells to a greater extent.
Pharmacokinetic data indicate that azacitidine is mainly administered subcutaneously or intravenously, with an oral formulation available for maintenance therapy in AML. The drug is primarily renally excreted, requiring consideration of renal function during treatment.
Key safety considerations include myelosuppression manifested as anemia, neutropenia, and thrombocytopenia. Additional adverse effects may include renal toxicity, tumor lysis syndrome, hepatotoxicity especially in patients with pre-existing hepatic impairment, and embryo-fetal toxicity. Monitoring of blood counts and organ function is standard in clinical use.
Azacitidine is classified among antimetabolites with a narrow therapeutic index and requires rigorous quality control during API sourcing. Sourcing should ensure consistency in purity, identity, and stability due to the compound’s sensitivity and critical role in therapeutic efficacy and safety. Compliance with current Good Manufacturing Practice (cGMP) and relevant pharmacopeial standards is essential for API procurement.
Identification & chemistry
| Generic name | Azacitidine |
|---|---|
| Molecule type | Small molecule |
| CAS | 320-67-2 |
| UNII | M801H13NRU |
| DrugBank ID | DB00928 |
Pharmacology
| Summary | Azacitidine is a cytosine nucleoside analogue that exerts antineoplastic effects primarily by inhibiting DNA methyltransferase, leading to DNA hypomethylation and altered gene expression. At higher concentrations, it incorporates into RNA and DNA, disrupting RNA metabolism, protein synthesis, and DNA replication, resulting in cytotoxicity in rapidly dividing cells. Its pharmacodynamic activity includes the restoration of normal differentiation and proliferation pathways through epigenetic modulation and direct cytotoxicity on abnormal hematopoietic cells. |
|---|---|
| Mechanism of action | Azacitidine (5-azacytidine) is a chemical analogue of the cytosine nucleoside present in DNA and RNA. It induces antineoplastic activity by inhibiting DNA methyltransferase at low doses and inducing cytotoxicity by incorporating itself into RNA and DNA at high doses. Covalent binding to DNA methyltransferase results in DNA hypomethylation and prevents DNA synthesis. On the other hand, the incorporation of azacitidine into RNA and DNA leads to cytotoxicity as follows: Following cellular uptake, azacitidine is phosphorylated by uridine-cytidine kinase to form 5-azacytidine monophosphate. Afterwards, pyrimidine monophosphate and diphosphate kinases phosphorylate 5-azacytidine monophosphate to form 5-azacytidine diphosphate and triphosphate, respectively. Azacitidine triphosphate is able to incorporate into RNA, disrupting RNA metabolism and protein synthesis. The reduction of azacytidine diphosphate leads to the formation of 5-aza-deoxycytidine diphosphate, which is then phosphorylated to form 5-azadeoxycitidine triphosphate, a compound able to incorporate into DNA and inhibit DNA synthesis. As a ribonucleoside, azacitidine incorporates into RNA to a larger extent than into DNA. Incorporating into RNA leads to the disassembly of polyribosomes, defective methylation and acceptor function of transfer RNA, and the inhibition of protein production, resulting in cell death. During the S-phase of the cell cycle, azacitidine exhibits the highest toxicity; however, the predominant mechanism of cytotoxicity has not been elucidated. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine. It is believed that azacitidine exerts its antineoplastic effects through direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. |
| Pharmacodynamics | The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis, and hypomethylation may restore normal function to genes critical for differentiation and proliferation. Genome-wide DNA methylation levels in bone marrow granulocytes were reduced in patients with juvenile myelomonocytic leukemia after the first treatment cycle of azacitidine (75 mg/m<sup>2</sup> or 2.5 mg/kg), confirming the DNA-hypomethylating activity of azacitidine. The use of azacitidine causes anemia, neutropenia and thrombocytopenia in adult patients with myelodysplastic syndrome and pediatric patients with juvenile myelomonocytic leukemia. Azacitidine may cause renal toxicity, tumor lysis syndrome and embryo-fetal toxicity. It may also lead to the development of hepatotoxicity in patients with severe pre-existing hepatic impairment. |
Targets
| Target | Organism | Actions |
|---|---|---|
| DNA (cytosine-5)-methyltransferase 1 | Humans | inhibitor |
| RNA | Humans | other |
| DNA | Humans | other |
ADME / PK
| Absorption | Azacitidine is rapidly absorbed after subcutaneous administration. In adult patients with myelodysplastic syndrome given a single subcutaneous dose of 75 mg/m<sup>2</sup> of azacitidine, the C<sub>max</sub> and T<sub>max</sub> were 750 ng/ml and 0.5 hours, respectively. Based on the area under the curve, the bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%. In 21 patients with cancer given subcutaneous azacitidine, the AUC and C<sub>max</sub> were approximately dose-proportional between 25 and 100 mg/m<sup>2</sup>. Multiple subcutaneous or intravenous doses of azacitidine are not expected to result in drug accumulation. |
|---|---|
| Half-life | The mean half-life of azacitidine after subcutaneous administration is 41 minutes. The mean elimination half-life of azacitidine and its metabolites was about 4 hours for intravenous and subcutaneous administrations. |
| Protein binding | Not available. |
| Metabolism | An in vitro study of azacitidine incubation in human liver fractions indicated that cytochrome P450 (CYP) enzymes do not participate in the metabolism of azacitidine. Azacitidine is metabolized through spontaneous hydrolysis and deamination mediated by cytidine deaminase. |
| Route of elimination | Azacitidine and its metabolites are mainly excreted through urine. In five cancer patients given radioactive azacitidine intravenously, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for less than 1% of administered radioactivity over three days. Following the subcutaneous administration of 14C-azacitidine, the mean excretion of radioactivity in urine was 50%. |
| Volume of distribution | In patients given an intravenous dose of azacitidine, the volume of distribution is 76 L. |
| Clearance | Azacitidine has an apparent subcutaneous clearance of 167 L/hour in adults. In pediatric patients, the geometric mean clearance was 21.8 L/hour. |
Formulation & handling
- Azacitidine is a small molecule API available for parenteral (intravenous and subcutaneous) and oral administration requiring formulation as lyophilized powders or tablets.
- The API has high water solubility and a low logP, supporting aqueous-based injectable formulations and oral dosage forms.
- Formulations should consider stability challenges associated with lyophilized powders and suspensions to maintain potency and minimize degradation during handling and storage.
Regulatory status
| Lifecycle | The API remains under patent protection in the United States until mid-2029 and mid-2030, limiting generic entry primarily in this market, while in the EU and Canada, where patents have expired or are not applicable, the product is at a more mature stage with generic competition present. |
|---|
| Markets | US, EU, Canada |
|---|
Supply Chain
| Supply chain summary | Azacitidine is primarily manufactured by a single originator company, with multiple entities involved in packaging. Its branded products have a presence across the US, EU, and Canadian markets. Existing patents in the United States extend until 2029 and 2030, indicating limited generic competition at present. |
|---|
Safety
| Toxicity | One case of overdose with azacitidine was reported during clinical trials. After receiving a single dose of 290 mg/m<sup>2</sup> of azacitidine intravenously (almost 4 times the recommended starting dose), a patient experienced diarrhea, nausea, and vomiting. These adverse events resolved without sequelae, and the correct dose was resumed the following day. In case of overdose, patients should be monitored with appropriate blood counts and receive supportive treatment as necessary. There is no known specific antidote for azacitidine overdosage. In mice, the oral LD<sub>50</sub> of azacitidine is 572 mg/kg, while the intravenous LD<sub>50</sub> is approximately 117 mg/kg. |
|---|
- Azacitidine exhibits dose-dependent toxicity with a reported overdose case at nearly fourfold the recommended dose resulting in transient gastrointestinal adverse effects
- No specific antidote for azacitidine overdosage is available
- Management involves monitoring hematologic parameters and providing supportive care
Azacitidine is a type of Antineoplastics
Antineoplastics are a crucial category of pharmaceutical active pharmaceutical ingredients (APIs) primarily used in the treatment of cancer. These powerful substances inhibit or destroy the growth of cancer cells, thus impeding the progression of malignancies.
Antineoplastics exert their therapeutic effects through various mechanisms. Some APIs interfere with DNA replication, inhibiting the division and proliferation of cancer cells. Others target specific proteins or enzymes involved in tumor growth, effectively blocking their function. Additionally, certain antineoplastic agents induce programmed cell death, known as apoptosis, in cancer cells.
These APIs find application in a wide range of cancer treatments, including chemotherapy, targeted therapy, immunotherapy, and hormone therapy. They are often administered in combination with other drugs to optimize therapeutic outcomes and minimize drug resistance.
Antineoplastics are typically synthesized through complex chemical processes, ensuring high purity and potency. Stringent quality control measures are implemented throughout manufacturing to meet regulatory standards and ensure patient safety.
Although antineoplastics offer significant benefits in treating cancer, they can also cause adverse effects due to their cytotoxic nature. Common side effects include bone marrow suppression, gastrointestinal disturbances, hair loss, and immune system suppression. Close monitoring and supportive care are essential to manage these side effects effectively.
In conclusion, antineoplastics are a vital category of pharmaceutical APIs used in the treatment of cancer. Through their diverse mechanisms of action, these compounds play a critical role in combating malignancies and improving patient outcomes.
Azacitidine API manufacturers & distributors
Compare qualified Azacitidine API suppliers worldwide. We currently have 17 companies offering Azacitidine API, with manufacturing taking place in 5 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Apino Pharma Co., Ltd. | Producer | China | China | BSE/TSE, cDMF, CoA, GMP, MSDS | 229 products |
| Chongqing Sintaho Pharmac... | Producer | China | China | BSE/TSE, CoA, EDMF/ASMF, FDA, GMP, ISO9001, MSDS, USDMF, WC | 42 products |
| Chongqing Taihao | Producer | China | China | CoA, WC | 7 products |
| Dr. Reddy's | Producer | India | India | BSE/TSE, CoA, EDMF/ASMF, FDA, GMP, JDMF, KDMF, MSDS, USDMF, WC | 170 products |
| Farmabios | Producer | Italy | Italy | CoA, GMP | 58 products |
| Hetero Labs | Producer | India | India | CoA, USDMF | 90 products |
| Intas Pharma | Producer | United Kingdom | Unknown | CoA, USDMF | 30 products |
| Jiangsu Hansoh Pharma | Producer | China | China | CoA, USDMF | 10 products |
| Laurus Labs | Producer | India | India | CoA, GMP, USDMF, WC | 50 products |
| MSN Labs. | Producer | India | India | CoA, GMP, USDMF, WC | 119 products |
| Polymed Therapeutics | Producer | United States | United States | CoA, USDMF | 11 products |
| Qilu Antibiotics | Producer | China | China | CoA, USDMF, WC | 33 products |
| SETV Global | Producer | India | India | CoA, FDA, GMP | 515 products |
| Shilpa Medicare Ltd | Producer | India | India | BSE/TSE, CoA, EDMF/ASMF, GMP, ISO9001, MSDS, USDMF, WC | 54 products |
| Shivalik Rasayan Ltd. | Producer | India | India | CoA, GMP, USDMF, WC, WHO-GMP | 13 products |
| Sicor | Producer | Italy | Italy | CoA, GMP | 47 products |
| Sun Pharma | Producer | India | India | CoA, USDMF | 219 products |
When sending a request, specify which Azacitidine API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
Use the list above to find high-quality Azacitidine API suppliers. For example, you can select GMP, FDA or ISO certified suppliers. Visit our help page to learn more about sourcing APIs via Pharmaoffer.
