Adriamycin for injection, usp

Name: Adriamycin for injection, usp

Description

Doxorubicin is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius .

Doxorubicin consists of a naphthacenequinone nucleus linked through a glycosidic bond at ring atom 7 to an amino sugar, daunosamine.

Chemically, doxorubicin hydrochloride is (8 S ,10 S )-10-[(3-Amino-2,3,6-trideoxy-(alpha)-L- lyxo -hexopyranosyl)-oxy]-8-glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The structural formula is as follows:

Doxorubicin binds to nucleic acids, presumably by specific intercalation of the planar anthracycline nucleus with the DNA double helix. The anthracycline ring is lipophilic, but the saturated end of the ring system contains abundant hydroxyl groups adjacent to the amino sugar, producing a hydrophilic center. The molecule is amphoteric, containing acidic functions in the ring phenolic groups and a basic function in the sugar amino group. It binds to cell membranes, as well as plasma proteins.

It is supplied in the hydrochloride form as a sterile red-orange lyophilized powder containing lactose and as a sterile parenteral, isotonic solution with sodium chloride for intravenous use only.

Adriamycin (DOXOrubicin HCI) for Injection, USP:

Each 10 mg lyophilized vial contains 10 mg of Doxorubicin Hydrochloride, USP and 50 mg of Lactose Monohydrate, NF.

Each 20 mg lyophilized vial contains 20 mg of Doxorubicin Hydrochloride, USP and 100 mg of Lactose Monohydrate, NF.

Each 50 mg lyophilized vial contains 50 mg of Doxorubicin Hydrochloride, USP and 250 mg of Lactose Monohydrate, NF.

Adriamycin (DOXOrubicin HCI) Injection, USP:

Each 2 mg/mL, 5 mL (10 mg) vial contains 10 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid.

Each 2 mg/mL, 10 mL (20 mg) vial contains 20 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid.

Each 2 mg/mL, 25 mL (50 mg) vial contains 50 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid.

Each 2 mg/mL, 100 mL (200 mg) multiple dose vial contains 200 mg Doxorubicin Hydrochloride, USP; Sodium Chloride 0.9% (to adjust tonicity) and Water for Injection q.s.; pH adjusted to 3 using Hydrochloric Acid.

Clinical Pharmacology

The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin cytocidal activity. Doxorubicin cellular membrane binding may effect a variety of cellular functions. Enzymatic electron reduction of doxorubicin by a variety of oxidases, reductases and dehydrogenases generate highly reactive species including the hydroxyl free radical OH·. Free radical formation has been implicated in doxorubicin cardiotoxicity by means of Cu (II) and Fe (III) reduction at the cellular level. Cells treated with doxorubicin have been shown to manifest the characteristic morphologic changes associated with apoptosis or programmed cell death. Doxorubicin-induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both.

Animal studies have shown activity in a spectrum of experimental tumors, immunosuppression, carcinogenic properties in rodents, induction of a variety of toxic effects, including delayed and progressive cardiac toxicity, myelosuppression in all species and atrophy to testes in rats and dogs.

Pharmacokinetic studies, determined in patients with various types of tumors undergoing either single or multi-agent therapy have shown that doxorubicin follows a multiphasic disposition after intravenous injection. The initial distributive half-life of approximately 5 minutes suggests rapid tissue uptake of doxorubicin, while its slow elimination from tissues is reflected by a terminal half-life of 20 to 48 hours. Steady-state distribution volumes exceed 20 to 30 L/kg and are indicative of extensive drug uptake into tissues. Plasma clearance is in the range of 8 to 20 mL/min/kg and is predominately by metabolism and biliary excretion. Approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the urine during the same time period. Binding of doxorubicin and its major metabolite, doxorubicinol to plasma proteins is about 74 to 76% and is independent of plasma concentration of doxorubicin up to 2 µM. Enzymatic reduction at the 7 position and cleavage of the daunosamine sugar yields aglycones which are accompanied by free radical formation, the local production of which may contribute to the cardiotoxic activity of doxorubicin. Disposition of doxorubicinol (DOX-OL) in patients is formation rate limited. The terminal half-life of DOX-OL is similar to doxorubicin. The relative exposure of DOX-OL, compared to doxorubicin ranges between 0.4 to 0.6. In urine, <3% of the dose was recovered as DOX-OL over 7 days.

A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in the men compared to the women (113 versus 45 L/hr). However, the terminal half-life of doxorubicin was longer in men compared to the women (54 versus 35 hrs).

In four patients , dose-independent pharmacokinetics have been shown for doxorubicin in the dose range of 30 to 70 mg/m 2 . Systemic clearance of doxorubicin is significantly reduced in obese women with ideal body weight greater than 130%. There was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with normal patients with less than 115% ideal body weight. The clearance of doxorubicin and doxorubicinol was also reduced in patients with impaired hepatic function. Doxorubicin was excreted in the milk of one lactating patient, with peak milk concentration at 24 hours after treatment being approximately 4.4 -fold greater than the corresponding plasma concentration . Doxorubicin was detectable in the milk up to 72 hours after therapy with 70 mg/m 2 of doxorubicin given as a 15 minute intravenous infusion and 100 mg/m 2 of cisplatin as a 26 hour intravenous infusion. The peak concentration of doxorubicinol in milk at 24 hours was 0.2 µM and AUC up to 24 hours was 16.5 µM.hr while the AUC for doxorubicin was 9.9 µM.hr.

Following administration of 10 to 75-mg/m 2 doses of doxorubicin to 60 children and adolescents ranging from 2 months to 20 years of age, doxorubicin clearance averaged 1443 +/- 114 mL/min/m 2 . Further analysis demonstrated that clearance in 52 children greater than 2 years of age (1540 mL/min/m 2 ) was increased compared with adults. However, clearance in infants younger than 2 years of age (813 mL/min/m 2 ) was decreased compared with older children and approached the range of clearance values determined in adults.

Doxorubicin does not cross the blood brain barrier.

Indications and Usage

Adriamycin (DOXOrubicin HCl) Injection, USP and Adriamycin (DOXOrubicin HCl) for Injection, USP have been used successfully to produce regression in disseminated neoplastic conditions such as acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms' tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin's disease, malignant lymphoma and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types.

Drug Interactions

Literature contains the following drug interactions with doxorubicin in humans: cyclosporine (Sandimmune) may induce coma and/or seizures, phenobarbital increases the elimination of doxorubicin, phenytoin levels may be decreased by doxorubicin, streptozocin (Zanosar) may inhibit the hepatic metabolism, and administration of live vaccines to immunosuppressed patients, including those undergoing cytotoxic chemotherapy, may be hazardous.

Paclitaxel:   Two published studies report that initial administration of paclitaxel infused over 24 hours followed by doxorubicin administered over 48 hours resulted in a significant decrease in doxorubicin clearance with more profound neutropenic and stomatitis episodes than the reverse sequence of administration.

Progesterone:   In a published study, progesterone was given intravenously to patients with advanced malignancies (ECOG PS < 2) at high doses (up to 10 g over 24 hours) concomitantly with a fixed doxorubicin dose (60 mg/m 2 ) via bolus. Enhanced doxorubicin-induced neutropenia and thrombocytopenia were observed.

Verapamil:   A study of the effects of verapamil on the acute toxicity of doxorubicin in mice revealed higher intial peak concentrations of doxorubicin in the heart with a higher incidence and severity of degenerative changes in cardiac tissue resulting in a shorter survival.

Cyclosporine:   The addition of cyclosporine to doxorubicin may result in increases in AUC for both doxorubicin and doxorubicinol possibly due to a decrease in clearance of parent drug and a decrease in metabolism of doxorubicinol. Literature reports suggest that adding cyclosporine to doxorubicin results in more profound and prolonged hematologic toxicity than doxorubicin alone. Coma and/or seizures have also been described.

Literature reports have also described the following drug interactions: phenobarbital increases the elimination of doxorubicin, phenytoin levels may be decreased by doxorubicin, streptozocin (Zanosar) may inhibit hepatic metabolism of doxorubicin, and administration of live vaccines to immunosuppressed patients including those undergoing cytotoxic chemotherapy may be hazardous.

Laboratory Tests:   Initial treatment with doxorubicin requires observation of the patient and periodic monitoring of complete blood counts, hepatic function tests, and radionuclide left ventricular ejection fraction (see WARNINGS ).

Like other cytotoxic drugs, doxorubicin may induce "tumor lysis syndrome" and hyperuricemia in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Formal long-term carcinogenicity studies have not been conducted with doxorubicin. Doxorubicin and related compounds have been shown to have mutagenic and carcinogenic properties when tested in experimental models (including bacterial systems, mammalian cells in culture, and female Sprague-Dawley rats).

The possible adverse effect on fertility in males and females in humans or experimental animals have not been adequately evaluated. Testicular atrophy was observed in rats and dogs.

Treatment-related acute myelogenous leukemia has been reported in patients treated with doxorubicin-containing adjuvant chemotherapy regimens (see ADVERSE REACTIONS , Hematologic ). The exact role of doxorubicin has not been elucidated. Pediatric patients treated with doxorubicin or other topoisomerase II inhibitors are at risk for developing acute myelogenous leukemia and other neoplasms. The extent of increased risk associated with doxorubicin has not been precisely quantified.

Pregnancy Category D:   (See WARNINGS .)

Nursing Mothers:   Because of the potential for serious adverse reactions in nursing infants from doxorubicin, mothers should be advised to discontinue nursing during doxorubicin therapy.

Pediatric Use:   Pediatric patients are at increased risk for developing delayed cardiotoxicity. Follow-up cardiac evaluations are recommended periodically to monitor for this delayed cardiotoxicity (see WARNINGS ).

Doxorubicin, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure. It may also contribute to gonadal impairment, which is usually temporary.

Overdosage

Acute overdosage with doxorubicin enhances the toxic effects of mucositis, leukopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antimicrobials, platelet transfusion and symptomatic treatment of mucositis. Use of hemopoietic growth factor (G-CSF, GM-CSF) may be considered.

The 200 mg Adriamycin (DOXOrubicin HCI) Injection, USP is packaged as a multiple dose vial, and caution should be exercised to prevent inadvertent overdosage.

Cumulative dosage with doxorubicin increases the risk of cardiomyopathy and resultant congestive heart failure (see WARNINGS ). Treatment consists of vigorous management of congestive heart failure with digitalis preparations, diuretics, and afterload reducers such as ACE inhibitors.

How Supplied

Adriamycin (DOXOrubicin HCl) for Injection, USP is supplied as a sterile red-orange lyophilized powder in single dose flip-top vials in the following package strengths:

NDC 55390-231-10:   10 mg vial; carton of 10.

NDC 55390-232-10:   20 mg vial; carton of 10.

NDC 55390-233-01:   50 mg vial; individually boxed.

Store unreconstituted vial at controlled room temperature, 15° to 30°C (59° to 86°F) [see USP]. Protect from light. Retain in carton until time of use. Discard unused portion.

Reconstituted Solution Stability:   After adding the diluent, the vial should be shaken and the contents allowed to dissolve. The reconstituted solution is stable for 7 days at room temperature and under normal room light (100 foot-candles) and 15 days under refrigeration (2° to 8°C). It should be protected from exposure to sunlight. Discard any unused solution from the 10 mg, 20 mg and 50 mg single dose vials. Unused solutions of the multiple dose vial remaining beyond the recommended storage times should be discarded.

Adriamycin (DOXOrubicin HCl) Injection, USP is supplied in single-dose, flip-top vials, as a red-orange solution containing Doxorubicin Hydrochloride, USP 2 mg/mL in the following package strengths:

NDC 55390-235-10:   510 mg in 5 mL; carton of 10.

NDC 55390-236-10:   20 mg in 10 mL; carton of 10.

NDC 55390-237-01:   50 mg in 25 mL; individually boxed.

Store refrigerated, 2° to 8°C (36° to 46°F).

Protect from light. Retain in carton until time of use. Discard unused portion.

Adriamycin (DOXOrubicin HCl) Injection, USP is supplied in a sterile, multiple dose, flip-top vial, as a red-orange solution containing Doxorubicin Hydrochloride, USP 2 mg/mL in the following package strength:

NDC 55390-238-01:   200 mg in 100 mL; individually boxed.

Store refrigerated, 2° to 8°C (36° to 46°F).

Protect from light. Retain in carton until contents are used.

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