BLEOMYCIN injection, powder, lyophilized, for solution

1. No Title 1572547975
2. No Title 1572553357
3. No Title 1572554308
4. Bleomycin
5. Warning
6. Description
7. Clinical Pharmacology
8. Indications And Usage
9. Contraindications
10. Warnings
11. Precautions
12. Adverse Reactions
13. Dosage And Administration
14. How Supplied
15. References
16. Principal Display Panel - 30 Unit Vial Label
17. Principal Display Panel - 30 Unit Vial Carton
18. Principal Display Panel - 15 Unit Vial Label
19. Principal Display Panel - 15 Unit Vial Carton
20. No Title 1572450763
21. Package/label Display Panel
22. Bleomycin For Injection, Usp
23. Principal Display Panel - 30 Unit Vial Label
24. Principal Display Panel - 30 Unit Vial Carton
25. Principal Display Panel - 15 Unit Vial Label
26. Principal Display Panel - 15 Unit Vial Carton
27. Important Drug Information
28. Overdosage
29. No Title 1572456254
30. No Title 1572456838
31. Vial Label 15 Units
32. Vial Label 30 Units
33. Serialization Image

No Title 1572547975 ⮝

3154

3155

Rx Only

No Title 1572553357 ⮝

BLEOMYCIN bleomycin injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70121-1567 Route of Administration INTRA-ARTERIAL, INTRAMUSCULAR, INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BLEOMYCIN SULFATE (UNII: 7DP3NTV15T) (BLEOMYCIN - UNII:40S1VHN69B) BLEOMYCIN 15000 [iU]

Inactive Ingredients Ingredient Name Strength HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM HYDROXIDE (UNII: 55X04QC32I)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:70121-1567-1 1 in 1 CARTON; Type 0: Not a Combination Product 06/20/2016

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date UNAPPROVED DRUG FOR USE IN DRUG SHORTAGE 06/20/2016

Labeler - Amneal Biosciences (079785595)

Revised: 7/2016 Document Id: 12921a48-db2b-4520-a2d6-1dacade3002e 34391-3 Set id: 38955939-8d1e-4db2-9aed-3bab72ca5f8f Version: 4 Effective Time: 20160711 Amneal Biosciences

No Title 1572554308 ⮝

Rx ONLY

Bleomycin ⮝

for Injection, USP

Rx only

Warning ⮝

WARNING It is recommended that bleomycin be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available. Pulmonary fibrosis is the most severe toxicity associated with bleomycin. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Its occurrence is higher in elderly patients and in those receiving greater than 400 units total dose, but pulmonary toxicity has been observed in young patients and those treated with low doses. A severe idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 1% of lymphoma patients treated with bleomycin.

Description ⮝

Bleomycin for Injection, USP is a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus. It is freely soluble in water. Bleomycin for injection is provided as a sterile, white to off-white, lyophilized cake or powder in vials for intramuscular, intravenous, or subcutaneous administration. Each 15 unit and 30 unit vial contains sterile bleomycin sulfate equivalent to 15 or 30 units of bleomycin, respectively. The pH range is 4.0 to 6.0 in a solution reconstituted with Sterile Water for Injection. Its chemical name is N1-[3-(dimethylsulphonio)propyl]bleomycin-amide (bleomycin A2) and N1-4-(guanidobutyl)bleomycinamide (bleomycin B2).

The molecular formula of bleomycin A2 is C55H84N17O21S3 and a calculated molecular weight of 1414. The molecular formula of bleomycin B2 is C55H84N20O21S2 and a calculated molecular weight of 1425. The structural formula is shown at right:

Note: A unit of bleomycin is equal to the formerly used milligram activity. The term milligram activity is a misnomer and was changed to units to be more precise.

Clinical Pharmacology ⮝

Mechanism of Action

Although the exact mechanism of action of bleomycin is unknown, available evidence indicates that the main mode of action is the inhibition of DNA synthesis with some evidence of lesser inhibition of RNA and protein synthesis.

Bleomycin is known to cause single, and to a lesser extent, double stranded breaks in DNA. In in vitro and in vivo experiments, bleomycin has been shown to cause cell cycle arrest in G2 and in mitosis.

When administered into the pleural cavity in the treatment of malignant pleural effusion, bleomycin acts as a sclerosing agent.

Pharmacokinetics

Absorption

Bleomycin is rapidly absorbed following either intramuscular, subcutaneous, intraperitoneal or intrapleural administration reaching peak plasma concentrations in 30 to 60 minutes. Systemic bioavailability of bleomycin is 100% and 70% following intramuscular and subcutaneous administrations, respectively, and 45% following both intraperitoneal and intrapleural administrations, compared to intravenous and bolus administration.

Following intramuscular doses of 1 to 10 units/m2, both peak plasma concentration and AUC increased in proportion with the increase of dose.

Following intravenous bolus administration of 30 units of bleomycin to one patient with a primary germ cell tumor of the brain, a peak CSF level was 40% of the simultaneously-obtained plasma level and was attained in two hours after drug administration. The area under the bleomycin CSF concentration x time curve was 25% of the area of the bleomycin plasma concentration x time curve.

Distribution

Bleomycin is widely distributed throughout the body with a mean volume of distribution of 17.5 L/m2 in patients following a 15 units/m2 IV bolus dose. Protein binding of bleomycin has not been studied.

Metabolism

Bleomycin is inactivated by a cytosolic cysteine proteinase enzyme, bleomycin hydrolase. The enzyme is widely distributed in normal tissues with the exception of the skin and lungs, both targets of bleomycin toxicity. Systemic elimination of the drug by enzymatic degradation is probably only important in patients with severely compromised renal function.

Excretion

The primary route of elimination is via the kidneys. About 65% of the administered intravenous dose is excreted in urine within 24 hours. In patients with normal renal function, plasma concentrations of bleomycin decline biexponentially with a mean terminal half-life of 2 hours following intravenous bolus administration. Total body clearance and renal clearance averaged 51 mL/min/m2 and 23 mL/min/m2, respectively. Following intrapleural administration to patients with normal renal function, a lower percentage of drug (40%) is recovered in the urine, as compared to that found in the urine after intravenous administration.

Special Populations

Age, Gender, and Race

The effects of age, gender, and race on the pharmacokinetics of bleomycin have not been evaluated.

Pediatric

Children of less than 3 years of age have higher total body clearance than in adults, 71 mL/min/m2 versus 51 mL/min/m2, respectively, following intravenous bolus administration. Children of more than 8 years of age have comparable clearance as in adults.

In children with normal renal function, plasma concentrations of bleomycin decline biexponentially as in adults. The volume of distribution and terminal half-life of bleomycin in children appears comparable to that in adults.

Renal Insufficiency

Renal insufficiency markedly alters bleomycin elimination. The terminal elimination half-life increases exponentially as the creatinine clearance decreases. Dosing reductions were proposed for patients with creatinine clearance values of <50 mL/min (see PRECAUTIONSand DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency

The effect of hepatic insufficiency on the pharmacokinetics of bleomycin has not been evaluated.

Drug Interactions

Drugs that Can Affect Renal Clearance

Because bleomycin is eliminated predominantly through renal excretion, the administration of nephrotoxic drugs with bleomycin may affect its renal clearance. Specifically, in one report of 2 children receiving concomitant cisplatin with bleomycin, total body clearance of bleomycin decreased from 39 to 18 mL/min/m2 as the cumulative dose of cisplatin exceeded 300 mg/m2. Terminal half-life of bleomycin also increased from 4.4 to 6 hours. Fatal bleomycin pulmonary toxicity has been reported in a patient with unrecognized cisplatin-induced oliguric renal failure.

Clinical Studies

Malignant Pleural Effusion

The safety and efficacy of bleomycin 60 units and tetracycline (1 g) as treatment for malignant pleural effusion were evaluated in a multicenter, randomized trial. Patients were required to have cytologically positive pleural effusion, good performance status (0,1,2), lung re-expansion following tube thoracostomy with drainage rates of 100 mL/24 hours or less, no prior intrapleural therapy, no prior systemic bleomycin therapy, no chest irradiation and no recent change in systemic therapy. Overall survival did not differ between the bleomycin (n=44) and tetracycline (n=41) groups. Of patients evaluated within 30 days of instillation, the recurrence rate was 36% (10/28) with bleomycin and 67% (18/27) with tetracycline (p=0.023). Toxicity was similar between groups.

Indications And Usage ⮝

Bleomycin for Injection, USP should be considered a palliative treatment. It has been shown to be useful in the management of the

Squamous Cell Carcinoma

Head and neck (including mouth, tongue, tonsil, nasopharynx, oropharynx, sinus, palate, lip, buccal mucosa, gingivae, epiglottis, skin, larynx), penis, cervix, and vulva. The response to bleomycin is poorer in patients with previously irradiated head and neck cancer.

Lymphomas

Hodgkin's disease, non-Hodgkin's lymphoma.

Testicular Carcinoma

Embryonal cell, choriocarcinoma, and teratocarcinoma.

Bleomycin for Injection, USP has also been shown to be useful in the management of:

Malignant Pleural Effusion

Bleomycin is effective as a sclerosing agent for the treatment of malignant pleural effusion and prevention of recurrent pleural effusions.

Contraindications ⮝

Bleomycin is contraindicated in patients who have demonstrated a hypersensitive or an idiosyncratic reaction to it.

Warnings ⮝

Patients receiving bleomycin must be observed carefully and frequently during and after therapy. It should be used with extreme caution in patients with significant impairment of renal function or compromised pulmonary function.

Pulmonary toxicities occur in 10% of treated patients. In approximately 1%, the nonspecific pneumonitis induced by bleomycin progresses to pulmonary fibrosis and death. Although this is age and dose related, the toxicity is unpredictable. Frequent roentgenograms are recommended (see ADVERSE REACTIONS: Pulmonary).

A severe idiosyncratic reaction (similar to anaphylaxis) consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 1% of lymphoma patients treated with bleomycin. Since these reactions usually occur after the first or second dose, careful monitoring is essential after these doses (see ADVERSE REACTIONS: Idiosyncratic Reactions).

Renal or hepatic toxicity, beginning as a deterioration in renal or liver function tests, have been reported. These toxicities may occur at any time after initiation of therapy.

Use in Pregnancy:

Teratogenic Effects: Pregnancy Category D:

Bleomycin can cause fetal harm when administered to a pregnant woman. It has been shown to be teratogenic in rats. Administration of intraperitoneal doses of 1.5 mg/kg/day to rats (about 1.6 times the recommended human dose on a unit/m2 basis) on days 6 to 15 of gestation caused skeletal malformations, shortened innominate artery and hydroureter. Bleomycin is abortifacient but not teratogenic in rabbits at intravenous doses of 1.2 mg/kg/day (about 2.4 times the recommended human dose on a unit/m2 basis) given on gestation days 6 to 18.

There have been no studies in pregnant women. If bleomycin is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with bleomycin.

Precautions ⮝

General

Patients with creatinine clearance values of less than 50 mL/min should be treated with caution and their renal function should be carefully monitored during the administration of bleomycin. Lower doses of bleomycin may be required in these patients than those with normal renal function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of bleomycin in humans is unknown. A study in F344-type male rats demonstrated an increased incidence of nodular hyperplasia after induced lung carcinogenesis by nitrosamines, followed by treatment with bleomycin. In another study where the drug was administered to rats by subcutaneous injection at 0.35 mg/kg weekly (3.82 units/m2 weekly or about 30% at the recommended human dose), necropsy findings included dose related injection site fibrosarcomas as well as various renal tumors. Bleomycin has been shown to be mutagenic both in vitro and in vivo. The effects of bleomycin on fertility have not been studied.

Pregnancy:

Teratogenic Effects: Pregnancy Category D.

(see WARNINGS)

Nursing mothers

It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued by women receiving bleomycin therapy.

Pediatric use

Safety and effectiveness of bleomycin in pediatric patients have not been established.

Geriatric use

In clinical trials, pulmonary toxicity was more common in patients older than 70 years than in younger patients (see BOXED WARNING, WARNINGS, and ADVERSE REACTIONS: Pulmonary). Other reported clinical experience has not identified other differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Bleomycin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse Reactions ⮝

Pulmonary

The most serious side effects are pulmonary adverse reactions, occurring in approximately 10% of treated patients. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Approximately 1% of patients treated have died of pulmonary fibrosis. Pulmonary toxicity is both dose and age related, being more common in patients over 70 years of age and in those receiving over 400 units total dose. This toxicity, however, is unpredictable and has been seen in young patients receiving low doses. Some published reports have suggested that the risk of pulmonary toxicity may be increased when bleomycin is used in combination with G-CSF (filgrastim) or other cytokines. However, randomized clinical studies completed to date have not demonstrated an increased risk of pulmonary complications in patients treated with bleomycin and G-CSF.

Because of lack of specificity of the clinical syndrome, the identification of patients with pulmonary toxicity due to bleomycin has been extremely difficult. The earliest symptom associated with bleomycin pulmonary toxicity is dyspnea. The earliest sign is fine rales.

Radiographically, bleomycin-induced pneumonitis produces nonspecific patchy opacities, usually of the lower lung fields. The most common changes in pulmonary function tests are a decrease in total lung volume and a decrease in vital capacity. However, these changes are not predictive of the development of pulmonary fibrosis.

The microscopic tissue changes due to bleomycin toxicity include bronchiolar squamous metaplasia, reactive macrophages, atypical alveolar epithelial cells, fibrinous edema, and interstitial fibrosis. The acute stage may involve capillary changes and subsequent fibrinous exudation into alveoli producing a change similar to hyaline membrane formation and progressing to a diffuse interstitial fibrosis resembling the Hamman-Rich syndrome. These microscopic findings are nonspecific; e.g., similar changes are seen in radiation pneumonitis and pneumocystic pneumonitis.

To monitor the onset of pulmonary toxicity, roentgenograms of the chest should be taken every 1 to 2 weeks (see WARNINGS). If pulmonary changes are noted, treatment should be discontinued until it can be determined if they are drug related. Recent studies have suggested that sequential measurement of the pulmonary diffusion capacity for carbon monoxide (DLco) during treatment with bleomycin may be an indicator of subclinical pulmonary toxicity. It is recommended that the DLco be monitored monthly if it is to be employed to detect pulmonary toxicities, and thus the drug should be discontinued when the DLco falls below 30% to 35% of the pretreatment value.

Because of bleomycin's sensitization of lung tissue, patients who have received bleomycin are at greater risk of developing pulmonary toxicity when oxygen is administered in surgery. While long exposure to very high oxygen concentrations is a known cause of lung damage, after bleomycin administration, lung damage can occur at lower concentrations that are usually considered safe. Suggested preventive measures are:

• 1.Maintain FI02 at concentrations approximating that of room air (25%) during surgery and the postoperative period.
• 2.Monitor carefully fluid replacement, focusing more on colloid administration rather than crystalloid.

Sudden onset of an acute chest pain syndrome suggestive of pleuropericarditis has been reported during bleomycin infusions. Although each patient must be individually evaluated, further courses of bleomycin do not appear to be contraindicated.

Pulmonary adverse events which may be related to the intrapleural administration of bleomycin have been reported.

Idiosyncratic Reactions

In approximately 1% of the lymphoma patients treated with bleomycin, an idiosyncratic reaction, similar to anaphylaxis clinically, has been reported. The reaction may be immediate or delayed for several hours, and usually occurs after the first or second dose (see WARNINGS). It consists of hypotension, mental confusion, fever, chills, and wheezing. Treatment is symptomatic including volume expansion, pressor agents, antihistamines, and corticosteroids.

Integument and Mucous Membranes

These adverse reactions have been reported in approximately 50% of treated patients. They consist of erythema, rash, striae, vesiculation, hyperpigmentation, and tenderness of the skin. Hyperkeratosis, nail changes, alopecia, pruritus, and stomatitis have also been reported. It was necessary to discontinue bleomycin therapy in 2% of treated patients because of these toxicities.

Scleroderma-like skin changes have been reported.

Skin toxicity is a relatively late manifestation usually developing in the second and third week of treatment after 150 to 200 units of bleomycin have been administered and appears to be related to the cumulative dose.

Intrapleural administration of bleomycin has been associated with local pain. Hypotension possibly requiring symptomatic treatment has been reported. Death has been reported in association with bleomycin pleurodesis in seriously ill patients.

Other

Vascular toxicities coincident with the use of bleomycin in combination with other antineoplastic agents have been reported. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (HUS) or cerebral arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud's phenomenon occurring in patients treated with bleomycin in combination with vinblastine with or without cisplatin or, in a few cases, with bleomycin as a single agent. It is currently unknown if the cause of Raynaud's phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any of these factors.

Fever, chills, and vomiting have been reported. Anorexia and weight loss have been reported and may persist long after termination of this medication. Pain at tumor site, phlebitis, and other local reactions have been reported.

Malaise has been reported.

Dosage And Administration ⮝

Because of the possibility of an anaphylactold reaction, lymphoma patients should be treated with 2 units or less for the first two doses. If no acute reaction occurs, then the regular dosage schedule may be followed.

The following dose schedule is recommended:

Squamous cell carcinoma, non-Hodgkin's lymphoma, testicular carcinoma 0.25 to 0.50 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly.

Hodgkin's disease 0.25 to 0.50 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly. After a 50% response, a maintenance dose of 1 unit daily or 5 units weekly intravenously or intramuscularly should be given.

Pulmonary toxicity of bleomycin appears to be dose-related with a striking increase when the total dose is over 400 units. Total doses over 400 units should be given with great caution.

Note: When bleomycin for injection is used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses.

Improvement of Hodgkin's disease and testicular tumors is prompt and noted within 2 weeks. If no improvement is seen by this time, improvement is unlikely. Squamous cell cancers respond more slowly, sometimes requiring as long as 3 weeks before any improvement is noted.

Malignant Pleural Effusion 60 units administered as a single dose bolus intrapleural injection (see Administration: Intrapleural).

Use in Patients with Renal Insufficiency

The following dosing reductions are proposed for patients with creatinine clearance (CrCL) values of less than 50 mL/min:

Patient CrCL (mL/min)	Bleomycin Dose (%)
50 and above	100
40 to 50	70
30 to 40	60
20 to 30	55
10 to 20	45
5 to 10	40

CrCL can be estimated from the individual patient s measured serum creatinine (Scr) values using the Cockroft and Gault formula:
Males CrCL = [weight x (140 Age)]/(72 x Scr)
Females CrCL = 0.85 x [weight x (140 Age)]/(72 x Scr)

Where CrCL in mL/min/1.73 m2, weight in kg, age in years, and Scr in mg/dL.

Administration

Bleomycin may be given by the intramuscular, intravenous, subcutaneous or intrapleural routes.

Administration Precautions

Caution should be exercised when handling bleomycin for injection. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing bleomycin for injection. If bleomycin for injection contacts the skin, immediately wash the skin thoroughly with soap and water. If contact with mucous membranes occurs, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below.

Intramuscular or Subcutaneous

The bleomycin 15 units vial should be reconstituted with 1 to 5 mL of Sterile Water for Injection, Sodium Chloride for Injection, 0.9%, or SterileBacteriostatic Water for Injection. The bleomycin 30 units vial should be reconstituted with 2 to 10 mL of the above diluents.

Intravenous

The contents of the 15 units or 30 units vial should be dissolved in 5 mL or 10 mL, respectively, of Sodium Chloride for Injection, 0.9%, and administered slowly over a period of 10 minutes.

Intrapleural

Sixty units of bleomycin are dissolved in 50 to 100 mL Sodium Chloride for Injection, 0.9%, and administered through a thoracostomy tube following drainage of excess pleural fluid and confirmation of complete lung expansion. The literature suggests that successful pleurodesis is, in part, dependent upon complete drainage of the pleural fluid and reestablishment of negative intrapleural pressure prior to instillation of a sclerosing agent. Therefore, the amount of drainage from the chest tube should be as minimal as possible prior to instillation of bleomycin. Although there is no conclusive evidence to support this contention, it is generally accepted that chest tube drainage should be less than 100 mL in a 24 hour period prior to sclerosis. However, bleomycin instillation may be appropriate when drainage is between 100 to 300 mL under clinical conditions that necessitate sclerosis therapy. The thoracostomy tube is clamped after bleomycin instillation. The patient is moved from the supine to the left and right lateral positions several times during the next four hours. The clamp is then removed and suction reestablished. The amount of time the chest tube remains in place following sclerosis is dictated by the clinical situation.

The intrapleural injection of topical anesthetics or systemic narcotic analgesia is generally not required.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

How Supplied ⮝

Bleomycin for Injection, USP is available as follows:

NDC 0143-9240-01, 15 units of bleomycin per vial as bleomycin sulfate USP.

NDC 0143-9241-01, 30 units of bleomycin per vial as bleomycin sulfate USP.

Stability

The sterile powder is stable under refrigeration 2 to 8 C (36 to 46 F) and should not be used after the expiration date is reached.

Bleomycin should not be reconstituted or diluted with D5W or other dextrose containing diluents. When reconstituted in D5W and analyzed by HPLC, bleomycin demonstrates a loss of A2 and B2 potency that does not occur when bleomycin is reconstituted in Sodium Chloride for Injection, 0.9%.

Bleomycin is stable for 24 hours at room temperature in Sodium Chloride.

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

For Product Inquiry call 1-877-845-0689.

References ⮝

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.

2.OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling occupational exposure to hazardous drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

3.American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.

4.Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society.

Manufactured by

THYMOORGAN PHARMAZIE GmbH,

Schiffgraben 23, 38690 Goslar, Germany

Distributed by

West-Ward Pharmaceuticals

Eatontown, NJ 07724 USA

Revised January 2017

127.207.022/00

Principal Display Panel - 30 Unit Vial Label ⮝

1 single dose vial
NDC 61703-323-22

Sterile
Rx only

Bleomycin for Injection, USP
30 units per vial

For Intravenous, Intramuscular,
Subcutaneous and Intrapleural Use

Caution: Cytotoxic -
Special Handling Procedures

Principal Display Panel - 30 Unit Vial Carton ⮝

VIAL

Hospira

1 single dose vial
NDC 61703-323-22

Sterile

Bleomycin for
Injection, USP

30 units per vial

Rx only

For Intravenous, Intramuscular,
Subcutaneous and
Intrapleural Use

Caution: Cytotoxic -
Special Handling Procedures

Principal Display Panel - 15 Unit Vial Label ⮝

1 single dose vial
NDC 61703-332-18

Sterile
Rx only

Bleomycin for Injection, USP
15 units per vial

For Intravenous, Intramuscular,
Subcutaneous and Intrapleural Use

Caution: Cytotoxic - Special Handling Procedures

Principal Display Panel - 15 Unit Vial Carton ⮝

VIAL

Hospira

1 single dose vial
NDC 61703-332-18

Sterile

Bleomycin for
Injection, USP

15 units per vial

Rx only

For Intravenous, Intramuscular,
Subcutaneous and
Intrapleural Use

Caution: Cytotoxic -
Special Handling Procedures

BLEOMYCIN bleomycin injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:61703-323 Route of Administration INTRAMUSCULAR, INTRAVENOUS, SUBCUTANEOUS, INTRAPLEURAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BLEOMYCIN SULFATE (UNII: 7DP3NTV15T) (BLEOMYCIN - UNII:40S1VHN69B) BLEOMYCIN 30 [USP'U]

Inactive Ingredients Ingredient Name Strength SULFURIC ACID (UNII: O40UQP6WCF) SODIUM HYDROXIDE (UNII: 55X04QC32I)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:61703-323-22 1 in 1 CARTON 04/10/2000 1 1 in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065031 04/10/2000

BLEOMYCIN bleomycin injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:61703-332 Route of Administration INTRAMUSCULAR, INTRAVENOUS, SUBCUTANEOUS, INTRAPLEURAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BLEOMYCIN SULFATE (UNII: 7DP3NTV15T) (BLEOMYCIN - UNII:40S1VHN69B) BLEOMYCIN 15 [USP'U]

Inactive Ingredients Ingredient Name Strength SULFURIC ACID (UNII: O40UQP6WCF) SODIUM HYDROXIDE (UNII: 55X04QC32I)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:61703-332-18 1 in 1 CARTON 04/11/2000 1 1 in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065031 04/11/2000

Labeler - Hospira, Inc. (141588017)

Establishment
Name	Address	ID/FEI	Business Operations
Hospira Australia Pty Ltd		758967652	ANALYSIS(61703-323, 61703-332) , LABEL(61703-323, 61703-332) , MANUFACTURE(61703-323, 61703-332) , PACK(61703-323, 61703-332)

Establishment
Name	Address	ID/FEI	Business Operations
Zydus Hospira Oncology Private Limited		676190889	ANALYSIS(61703-323, 61703-332) , LABEL(61703-323, 61703-332) , MANUFACTURE(61703-323, 61703-332) , PACK(61703-323, 61703-332)

Revised: 3/2019 Document Id: beb7aa5d-bc4f-4c7f-a0ff-606833f0ed89 34391-3 Set id: 905e0984-2ce3-481c-b1a0-0ef0a616479a Version: 17 Effective Time: 20190311 Hospira, Inc.

No Title 1572450763 ⮝

3154

3155

Rx Only

Package/label Display Panel ⮝

Bleomycin for Injection USP 30 Units/Single Dose Vial Carton Text

NDC 0703-3155-01 Rx only

BLEOMYCIN

for Injection USP

equivalent to

30 Units/Vial

Bleomycin

CAUTION: Cytotoxic

Special Handling Procedures

Single Dose Vial

For IV, IM, SC or

Intrapleural Use

TEVA

BLEOMYCIN bleomycin injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0703-3154 Route of Administration INTRAMUSCULAR, INTRAPLEURAL, INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BLEOMYCIN SULFATE (UNII: 7DP3NTV15T) (BLEOMYCIN - UNII:40S1VHN69B) BLEOMYCIN 15 [USP'U]

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0703-3154-01 1 in 1 CARTON 06/30/2000 1 1 in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065033 06/30/2000

BLEOMYCIN bleomycin injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0703-3155 Route of Administration INTRAMUSCULAR, INTRAPLEURAL, INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BLEOMYCIN SULFATE (UNII: 7DP3NTV15T) (BLEOMYCIN - UNII:40S1VHN69B) BLEOMYCIN 30 [USP'U]

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0703-3155-01 1 in 1 CARTON 06/30/2000 1 1 in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065033 06/30/2000

Labeler - Teva Parenteral Medicines, Inc. (794362533)

Revised: 2/2016 Document Id: 2070a6c8-eb51-4e74-abd2-21b2aab55b5f 34391-3 Set id: 2ef2901b-e3ee-47ba-81d9-48c6668fd19b Version: 9 Effective Time: 20160201 Teva Parenteral Medicines, Inc.

Bleomycin For Injection, Usp ⮝

Rx only

Principal Display Panel - 30 Unit Vial Label ⮝

1 single dose vial
Sterile
NDC 0409-0323-20

Bleomycin for Injection, USP
30 units per vial

For Intravenous, Intramuscular,
Subcutaneous and Intrapleural Use

Rx only

Caution: Cytotoxic -
Special Handling Procedures

novaplus

Novaplus is a registered trademark of Vizient, Inc.

Principal Display Panel - 30 Unit Vial Carton ⮝

1 single dose vial
Sterile
NDC 0409-0323-20

Bleomycin for
Injection, USP
30 units per vial

For Intravenous,
Intramuscular,
Subcutaneous and
Intrapleural Use

Rx only

novaplus

Caution: Cytotoxic -
Special Handling Procedures

Principal Display Panel - 15 Unit Vial Label ⮝

1 single dose vial
Sterile
NDC 0409-0332-20

Bleomycin for Injection, USP
15 units per vial

For Intravenous, Intramuscular,
Subcutaneous and Intrapleural Use

Rx only

Caution: Cytotoxic -
Special Handling Procedures

novaplus

Novaplus is a registered
trademark of Vizient, Inc.

Principal Display Panel - 15 Unit Vial Carton ⮝

1 single dose vial
Sterile
NDC 0409-0332-20

Bleomycin for
Injection, USP
15 units per vial

For Intravenous,
Intramuscular,
Subcutaneous and
Intrapleural Use

Rx only

novaplus

Caution: Cytotoxic -
Special Handling Procedures

BLEOMYCIN bleomycin injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0409-0323 Route of Administration INTRAMUSCULAR, INTRAVENOUS, SUBCUTANEOUS, INTRAPLEURAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BLEOMYCIN SULFATE (UNII: 7DP3NTV15T) (BLEOMYCIN - UNII:40S1VHN69B) BLEOMYCIN 30 [USP'U]

Inactive Ingredients Ingredient Name Strength SULFURIC ACID (UNII: O40UQP6WCF) SODIUM HYDROXIDE (UNII: 55X04QC32I)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0409-0323-20 1 in 1 CARTON 04/25/2018 1 1 in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065031 04/25/2018

BLEOMYCIN bleomycin injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0409-0332 Route of Administration INTRAMUSCULAR, INTRAVENOUS, SUBCUTANEOUS, INTRAPLEURAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BLEOMYCIN SULFATE (UNII: 7DP3NTV15T) (BLEOMYCIN - UNII:40S1VHN69B) BLEOMYCIN 15 [USP'U]

Inactive Ingredients Ingredient Name Strength SULFURIC ACID (UNII: O40UQP6WCF) SODIUM HYDROXIDE (UNII: 55X04QC32I)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0409-0332-20 1 in 1 CARTON 04/25/2018 1 1 in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065031 04/25/2015

Labeler - Hospira, Inc. (141588017)

Establishment
Name	Address	ID/FEI	Business Operations
Hospira Australia Pty Ltd		758967652	ANALYSIS(0409-0323, 0409-0332) , LABEL(0409-0323, 0409-0332) , MANUFACTURE(0409-0323, 0409-0332) , PACK(0409-0323, 0409-0332)

Establishment
Name	Address	ID/FEI	Business Operations
Zydus Hospira Oncology Private Limited		676190889	ANALYSIS(0409-0323, 0409-0332) , LABEL(0409-0323, 0409-0332) , MANUFACTURE(0409-0323, 0409-0332) , PACK(0409-0323, 0409-0332)

Revised: 4/2019 Document Id: 4942d4a5-d2e7-4fdb-8a66-512f3eae7969 34391-3 Set id: e629ba5a-4e08-4249-9551-af6dbd98a7e4 Version: 7 Effective Time: 20190401 Hospira, Inc.

Important Drug Information ⮝

July 5, 2016

Re: Temporary importation of Bleomycin Sulfate Powder for Injection, 15,000 International Units (IU) to address drug shortage issue

Dear Healthcare Professional,

IMPORTANT NOTE: Each vial of Amneal Biosciences product contains 15,000 IU of Bleomycin Sulfate Powder for Injection, which is equivalent to Bleomycin Sulfate USP 15 units (1000 IU of Bleomycin Sulfate Powder for Injection = 1 unit of Bleomycin Sulfate USP). Prescribers and pharmacists must be alert to this difference in labeled units in order to prevent medication errors. Appropriate quality assurance measures should be enacted to reduce the risk of medication errors.

Due to the current critical shortage of Bleomycin Sulfate for Injection, USP, 15 units and 30 units per vial in the United States (U.S.) market, Amneal Biosciences is coordinating with the U.S. Food and Drug Administration (FDA) to increase the availability of Bleomycin Sulfate for Injection, USP, 15 units per vial.

Amneal Biosciences has initiated temporary importation of a non-FDA approved product, Bleomycin Sulfate Powder for Injection 15,000 IU per vial to the U.S. market: lot numbers GE50604, GE60003, GE60012. The Bleomycin Sulfate Powder for Injection 15,000 IU product being distributed by Amneal Biosciences was manufactured by Cipla Ltd. from its FDA-inspected facility in Verna, Goa, India, for Amneal Pharma Australia Pty Ltd and was sold in Australia under the WIllow Pharmaceutical label.

At this time, no other entity except Amneal Biosciences is authorized by the FDA to import or distribute Amneal Pharma Australia Pty Ltd. s Bleomycin Sulfate Powder for Injection 15,000 IU product. FDA has not approved the Bleomycin Sulfate Powder for Injection 15,000 IU product being distributed by Amneal Biosciences in the United States.

Amneal Biosciences Bleomycin Sulfate Powder for Injection 15,000 IU product contains the same active ingredient, bleomycin sulfate, in the same strength as the U.S. FDA-approved Bleomycin Sulfate for Injection, USP, 15 units per vial.

In the U.S., the labeling for Bleomycin Sulfate for Injection includes the following indications: i) squamous cell carcinoma; ii) non-Hodgkin lymphoma; iii) testicular carcinoma; iv) Hodgkin lymphoma; v) malignant pleural effusion.

Bleomycin Sulfate Powder for Injection 15,000 IU product being distributed by Amneal Biosciences is approved in Australia and is dispensed with a Medication Guide. The information on the medication guide differs from the full prescribing information for the current U.S. FDA reference listed drug (RLD). Two key differences between the two package inserts is that the U.S. FDA-approved label uses different units from the Amneal Biosciences label and the Amneal Australia label does not include an indication for malignant pleural effusions. Additionally, the U.S. FDA-approved label provides weight-based dosing information as well as body surface area-based dosage, whereas the imported product label contains only BSA-based dosing information.

This letter is not intended as a complete description of the benefits and risks related to the use of Bleomycin Sulfate Powder for Injection 15,000 IU. Please refer to the package insert for the U.S. FDA-approved Bleomycin Sulfate for Injection, USP for full prescribing information.

Please note that the barcode used for Amneal Biosciences Bleomycin Sulfate Powder for Injection, 15,000 IU product may not be appropriately recognized by scanning systems used in the United States. Institutions should confirm that barcode systems do not provide incorrect information when the product is scanned. Alternative procedures should be followed to assure that the correct drug product is being used and administered to individual patients.

The Bleomycin Sulfate Powder for Injection 15,000 IU product distributed by Amneal Biosciences should be handled exactly as you have handled the U.S. FDA-approved Bleomycin Sulfate for Injection, USP. Refrigerate unopened vials at 2 C to 8 C (36 F to 46 F). The Bleomycin Sulfate Powder for Injection 15,000 IU product distributed by Amneal Biosciences should not be reconstituted or diluted with D5W or other dextrose-containing diluents.

To order Bleomycin Sulfate Powder for Injection, 15,000 IU product distributed by Amneal Biosciences, health care professionals can order the product from their wholesaler/distributor of choice.

To report adverse events or medication errors, or for answers to medical and technical inquiries for patients who have used Amneal Biosciences Bleomycin Sulfate Powder for Injection, 15,000 IU product, please contact Amneal Biosciences Drug Safety by telephone at 1-855-266-3251 Monday through Friday from 9:00-5:30 EST, or email at biosciencesdrugsafety@amneal.com.

Adverse events or quality problems experienced with the use of this product may also be reported to the FDA s MedWatch Adverse Event Reporting Program either online, or regular mail, or by fax:

• Complete and submit the report Online: www.fda.gov/medwatch/report.htm
• Regular mail or Fax: Download form www.fda.gov/MedWatch/getforms.htm or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178.

For full U.S. FDA reference listed drug (RLD) prescribing information for Bleomycin Sulfate for Injection, USP, including the BOXED WARNING, please visit:

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b5806c40-12ce-48e3-8abd-9f8997ef4428

For full prescribing information for Amneal Bioscience s Bleomycin Sulfate Powder for Injection 15,000 IU product, please visit:

http://tga-search.clients.funnelback.com/s/search.html?collection=tga-artg&profile=record&meta_i=157341

Sincerely,

Charles D. Lucarelli

President

Amneal Biosciences LLC

Overdosage ⮝

Symptoms: There has been no reported case of over dosage. The acute reaction would probably include hypotension, fever, rapid pulse and general symptoms of shock.

Treatment. There is no specific antidote for bleomycin Over dosage. Treatment should be symptomatic and supportive. In the everit0t respiratory complications treatment with a corticosteroid may be beneficial and the administration of a broad spectrum antibiotic is advisable.

Bleomycin is probably not dialyzable.

In case of Overdose, immediately contact the Poisons Information Centre for advice. (In Australia, call 131 126.)

No Title 1572456254 ⮝

Manufactured by:

Cipla Ltd

Verna Industrial Estate

Verna, Goa

403722

India

Sponsor:

Amneal Pharma Australia Pty Ltd

12 River Street

SOUTH YARRA, VIC, 3141

Australia

Revision: November, 2011

No Title 1572456838 ⮝

Rx ONLY

Vial Label 15 Units ⮝

Bleomycin 15 units/vial

NDC 0143-9240-01 Rx only

Bleomycin for Injection, USP
Equivalent to

15 units/vial
Bleomycin
FOR IM, IV, SC or
INTRAPLEURAL USE

Cytotoxic

Vial Label 30 Units ⮝

Bleomycin for Injection 30 units/vial

NDC 0143-9241-01 Rx only

Bleomycin for Injection, USP
Equivalent to

30 units/vial
Bleomycin
FOR IM, IV, SC or
INTRAPLEURAL USE

Cytotoxic

Serialization Image ⮝

Representative Carton Serialization Image

BLEOMYCIN bleomycin injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0143-9240 Route of Administration INTRAMUSCULAR, INTRAPLEURAL, INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BLEOMYCIN SULFATE (UNII: 7DP3NTV15T) (BLEOMYCIN - UNII:40S1VHN69B) BLEOMYCIN 15 [USP'U]

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0143-9240-01 1 in 1 BOX, UNIT-DOSE 01/09/2018 1 1 in 1 VIAL; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065042 01/09/2018

BLEOMYCIN bleomycin injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0143-9241 Route of Administration INTRAMUSCULAR, INTRAPLEURAL, INTRAVENOUS, SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BLEOMYCIN SULFATE (UNII: 7DP3NTV15T) (BLEOMYCIN - UNII:40S1VHN69B) BLEOMYCIN 30 [USP'U]

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0143-9241-01 1 in 1 BOX, UNIT-DOSE 01/09/2018 1 1 in 1 VIAL; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065042 01/09/2018

Labeler - West-Ward Pharmaceuticals Corp (001230762)

Revised: 12/2018 Document Id: 969b2bd2-8d8f-4759-9302-047062ce61f7 34391-3 Set id: cccfb763-79fa-4186-89fb-d8d061d3c161 Version: 3 Effective Time: 20181213 West-Ward Pharmaceuticals Corp