Hikma launches Azacitidine for Injection

London, 10 September, 2020 – Hikma Pharmaceuticals PLC (Hikma), the multinational pharmaceutical company, has launched Azacitidine for Injection, 100mg, the generic version of Vidaza® in the United States through its US affiliate, Hikma Pharmaceuticals USA Inc.

Press Release Product 10 September 2020

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According to IQVIA, US sales of Azacitidine for Injection, 100mg, were approximately $82 million in the 12 months ending July 2020.

Azacitidine for Injection is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (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).

Hikma is the third largest US supplier of generic injectable medicines by volume, with a growing portfolio of over 100 products. Today one in every six injectable generic medicines used in US hospitals is a Hikma product.

Important Safety Information for Azacitidine for Injection, 100mg:

 

CONTRAINDICATIONS

Advanced Malignant Hepatic Tumors

Azacitidine for Injection is contraindicated in patients with advanced malignant hepatic tumors.

 

Hypersensitivity to Azacitidine or Mannitol

Azacitidine for Injection is contraindicated in patients with a known hypersensitivity to azacytidine or mannitol.

WARNINGS & PRECAUTIONS

  • Azacitidine for Injection causes anemia, neutropenia and throm Monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, adjust dosage for subsequent cycles based on nadir counts and hematologic response.
  • Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disea Patients with extensive tumor burden due to metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/L.
  • Azacitidine is contraindicated in patients with advanced malignant hepatic tum Monitor liver chemistries prior to initiation of therapy and with each cycle.
  • Safety and effectiveness of Azacitidine for Injection in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials.
  • Renal toxicity ranging from elevated serum creatinine to renal failure and death have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for non-MDS conditio
  • Renal tubular acidosis, defined as a fall in serum bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in 5 patients with CML treated with azacitidine and etoposide. Monitor serum creatinine and electrolytes prior to initiation of therapy and with each If unexplained reductions in serum bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, reduce or hold the dose.
  • Patients with renal impairment may be at increased risk for renal toxicity. Also, azacitidine and its metabolites are primarily excreted by the kidne Therefore, monitor these patients closely for toxicity. Patients with MDS and renal impairment were excluded from the clinical studies.
  • Azacitidine for Injection may cause fatal or serious tumor lysis syndrome, including in patients with Tumor lysis syndrome may occur despite concomitant use of allopurinol. Assess baseline risk and monitor and treat as appropriate.
  • Based on the mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when administered to a pregnant wom Azacitidine administered to pregnant rats via a single intraperitoneal (IP) dose approximating 8% of the recommended human daily dose caused fetal death and anomalies.
  • Advise females with reproductive potential to avoid pregnancy during treatment with Azacitidine for Injection. Men should be advised to not father a child while receiving treatment with Azacitidine for Injection.

ADVERSE REACTIONS

The following adverse reactions are described in other labeling sections:

  • Anemia, Neutropenia and Thrombocytopenia
  • Hepatotoxocity in Patients with Severe Pre-existing Hepatic Impairment
  • Renal Toxicity
  • Tumor Lysis Syndrome
  • Embryo-Fetal Risk

Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation,  neutropenia, ecchymosis. The most common adverse reactions by intravenous route also included  petechiae, rigors, weakness and hypokalemia.

Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (Subcutaneous or Intravenous Route):

Discontinuation: leukopenia, thrombocytopenia, neutropenia.

Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.

Dose Reduced: leukopenia, neutropenia, thrombocytopenia.

Refer to package insert for Adverse Reactions in Clinical Trials: the adverse reactions are broken down into most frequently observed (≥ 5.0% in treated patients) and less frequently observed (< 5% in treated patients).

The following adverse reactions have been identified during postmarketing use of Azacitidine for Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Interstitial lung disease
  • Tumor lysis syndrome
  • Injection site necrosis
  • Sweet’s syndrome (acute febrile neutrophilic dermatosis)
  • Necrotizing fasciitis (including fatal cases)
  • Differentiation syndrome

DRUG INTERACTIONS

No formal clinical drug interaction studies with azacitidine have been conducted.

An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by the liver. Whether azacitidine metabolism may be affected by known microsomal enzyme inhibitors or inducers has not been studied.

An in vitro study with cultured human hepatocytes indicated that azacitidine at concentrations up to 100 µM (IV Cmax = 10.6 µM) does not cause any inhibition of CYP2B6 and CYP2C8. The potential of azacitidine to inhibit other cytochrome P450 (CYP) enzymes is not known.

In vitro studies with human cultured hepatocytes indicate that azacitidine at concentrations of 1.0 µM to 100 µM does not induce CYP 1A2, 2C19, or 3A4/5.

 

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

Based on its mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when administered to a pregnant woman. There are no data on the use of azacitidine in pregnant women. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses lower than the recommended human daily dose. Advise pregnant women of the potential risk to the fetus.

Lactation

Risk Summary

There is no information regarding the presence of azacitidine in human milk, the effects of Azacitidine for Injection on the breastfed infant, or the effects of Azacitidine for Injection on milk production. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for azacitidine in animal studies and the potential for serious adverse reactions in nursing infants from Azacitidine for Injection, advise patients not to breastfeed during treatment with Azacitidine for Injection.

Females and Males of Reproductive Potential

Based on its mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating Azacitidine for Injection. Advise females of reproductive potential to avoid pregnancy during treatment with Azacitidine for Injection. Males with female sexual partners of reproductive potential should not father a child and should use effective contraception during treatment with Azacitidine for Injection. Based on animal data, azacitidine could have an effect on male or female fertility.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition, there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients.

Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients < 65 years of age and patients 65 years of age and older.

Elderly patients are more likely to have decreased renal function. Monitor renal function in these patients.

DOSAGE AND ADMINISTRATION

Refer to package insert for dosage and administration instructions specific to the First Treatment Cycle, Subsequent Treatment Cycles, Dosage Adjustment Based on Hematology Laboratory Values, Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity, and Use in Geriatric Patients.

Preparation of Azacitidine for Injection

Azacitidine for Injection is a cytotoxic drug. Follow applicable special handling and disposal

procedures.

The Azacitidine for Injection vial is single-dose and does not contain any preservatives. Discard unused portions of each vial properly. Do not save any unused portions for later administration.

Instructions for Subcutaneous Administration

Refer to package insert for dosage and administration instructions specific to Subcutaneous Administration: Reconstitution, Preparation for Immediate Subcutaneous Administration, Preparation for Delayed Subcutaneous Administration, Subcutaneous Administration, and Suspension Stability.

Instructions for Intravenous Administration

Refer to package insert for dosage and administration instructions specific to Intravenous Administration: Reconstitution, Intravenous Solution Incompatibility, Intravenous Administration, and Solution Stability.

Handling and Disposal

Azacitidine for Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.

OVERDOSAGE

One case of overdose with Azacitidine for Injection was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m2, almost 4 times the recommended starting dose. The events resolved without sequelae, and the correct dose was resumed the following day. In the event of overdosage, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for Azacitidine for Injection overdosage.

 

 

ENDING INFORMATION

Patient Counseling Information should be shared with the patient prior to administration.

For additional information, please refer to the Package Insert for full prescribing information, available on www.hikma.com.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch or call 1-800-FDA-1088.

Manufactured by:

THYMOORGAN PHARMAZIE GmbH

Schiffgraben 23, 38690 Goslar, Germany

Distributed by:

West-Ward, A Hikma Company (now Hikma Pharmaceuticals USA Inc.)

Eatontown, NJ 07724 USA

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