Doxorubicin
Generic Name: Doxorubicin
hydrochloride
Dosage Form: injection, solution
WARNING:
CARDIOMYOPATHY, SECONDARY MALIGNANCIES, EXTRAVASATION AND TISSUE NECROSIS, and
SEVERE MYELOSUPPRESSION
· Cardiomyopathy:
Myocardial damage, including acute left ventricular failure can occur with Doxorubicin hydrochloride. The
risk of cardiomyopathy is proportional to the cumulative exposure with
incidence rates from 1% to 20% for cumulative doses ranging from 300 mg/m2 to
500 mg/m2 when Doxorubicin
hydrochloride is administered every 3 weeks. The risk of cardiomyopathy is
further increased with concomitant cardiotoxic therapy. Assess LVEF before and
regularly during and after treatment with Doxorubicin
hydrochloride [see Warnings
and Precautions (5.1)].
· Secondary
Malignancies: Secondary acute myelogenous leukemia (AML) and myelodysplastic
syndrome (MDS) occur at a higher incidence in patients treated with
anthracyclines, including Doxorubicin
hydrochloride [see Warnings
and Precautions (5.2)].
· Extravasation
and Tissue Necrosis: Extravasation of Doxorubicin hydrochloride can result in severe local tissue injury
and necrosis requiring wide excision of the affected area and skin grafting.
Immediately terminate the drug and apply ice to the affected area [see Warnings
and Precautions (5.3)].
· Severe
myelosuppression resulting in serious infection, septic shock, requirement for
transfusions, hospitalization, and death may occur [see Warnings
and Precautions (5.4)].
Indications and Usage for Doxorubicin
Adjuvant
Breast Cancer
Doxorubicin hydrochloride
injection, USP is indicated as a component of multi-agent adjuvant chemotherapy
for treatment of women with axillary lymph node involvement following resection
of primary breast cancer [see Clinical
Studies (14)].
Other Cancers
Doxorubicin hydrochloride
injection, USP is indicated for the treatment of
·
acute lymphoblastic leukemia
·
acute myeloblastic leukemia
·
Hodgkin lymphoma
·
non-Hodgkin lymphoma (NHL)
·
metastatic breast cancer
·
metastatic Wilms’ tumor
·
metastatic neuroblastoma
·
metastatic soft tissue sarcoma
·
metastatic bone sarcoma
·
metastatic ovarian carcinoma
·
metastatic transitional cell
bladder carcinoma
·
metastatic thyroid carcinoma
·
metastatic gastric carcinoma
·
metastatic bronchogenic
carcinoma
Doxorubicin Dosage and Administration
Recommended
Dose
Adjuvant Breast Cancer
The recommended dose of
Doxorubicin hydrochloride injection is 60 mg/m2 administered as an
intravenous bolus on day 1 of each 21-day treatment cycle, in combination with
cyclophosphamide, for a total of four cycles [see Clinical
Studies (14)].
Metastatic
Disease, Leukemia, or Lymphoma
·
The recommended dose of
Doxorubicin hydrochloride injection when used as a single agent is 60 to 75
mg/m2 intravenously
every 21 days.
·
The recommended dose of
Doxorubicin hydrochloride injection, when administered in combination with other
chemotherapy drugs, is 40 to 75 mg/m2 intravenously every 21 to 28 days.
·
Consider use of the lower
Doxorubicin dose in the recommended dose range or longer intervals between
cycles for heavily pretreated patients, elderly patients, or obese patients.
·
Cumulative doses above 550
mg/m2 are
associated with an increased risk of cardiomyopathy [see Warnings
and Precautions (5.1)].
Dose
Modifications
Cardiac Impairment
Discontinue Doxorubicin in
patients who develop signs or symptoms of cardiomyopathy.
Hepatic
Impairment
Doxorubicin hydrochloride
injection is contraindicated in patients with severe hepatic impairment
(Child-Pugh Class C or serum bilirubin greater than 5.0 mg/dL) [see Contraindications
(4)].
Decrease the dose of
Doxorubicin hydrochloride injection in patients with elevated serum total bilirubin
concentrations as follows:
|
Serum Bilirubin Concentration
|
Doxorubicin Hydrochloride Injection Dose Reduction
|
|
1.2 to 3.0 mg/dL
|
50 %
|
|
3.1 to 5.0 mg/dL
|
75 %
|
|
greater than 5.0
mg/dL
|
Do not initiate
Doxorubicin hydrochloride injection
Discontinue Doxorubicin hydrochloride injection
|
|
[see Warnings and Precautions (5.5) and Use in Specific Population (8.7)]
|
Preparation
and Administration
Preparation for Continuous Intravenous Infusion
Dilute Doxorubicin
hydrochloride injection solution in 0.9% Sodium Chloride Injection, USP or 5%
Dextrose Injection, USP. Protect from light following preparation until
completion of infusion.
Administration
Visually inspect parenteral
drug products for particulate matter and discoloration prior to administration,
whenever solution and container permit. Discard if the solution is discolored,
cloudy, or contains particulate matter.
Storage of vials of
Doxorubicin hydrochloride injection following reconstitution under refrigerated
conditions can result in the formation of a gelled product. Place gelled
product at room temperature [15º to 30ºC (59º to 86ºF)] for 2 to 4 hours to
return the product to a slightly viscous, mobile solution.
Administration
by Intravenous Injection:
·
Administer Doxorubicin
hydrochloride injection as an intravenous injection through a central intravenous
line or a secure and free-flowing peripheral venous line containing 0.9% Sodium
Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 5% Dextrose
Injection, USP.
·
Administer Doxorubicin
hydrochloride injection intravenously over 3 to 10 minutes. Decrease the rate
of Doxorubicin hydrochloride injection administration if erythematous streaking
along the vein proximal to the site of infusion or facial flushing occur.
Administration by Continuous Intravenous Infusion:
·
Infuse only through a central
catheter. Decrease the rate of Doxorubicin hydrochloride injection
administration if erythematous streaking along the vein proximal to the site of
infusion or facial flushing occur.
·
Protect from light from
preparation for infusion until completion of infusion.
Management of Suspected Extravasation
Discontinue
Doxorubicin hydrochloride injection for burning or stinging sensation or other
evidence indicating perivenous infiltration or extravasation. Manage confirmed
or suspected extravasation as follows:
·
Do not remove the needle until
attempts are made to aspirate extravasated fluid.
·
Do not flush the line.
·
Avoid applying pressure to the
site.
·
Apply ice to the site
intermittently for 15 min 4 times a day for 3 days.
·
If the extravasation is in an
extremity, elevate the extremity.
·
In adults, consider
administration of dexrazoxane [see Warnings
and Precautions (5.3)].
Incompatibility
with Other Drugs
Do not admix Doxorubicin
hydrochloride injection with other drugs. If Doxorubicin hydrochloride
injection is mixed with heparin or fluorouracil a precipitate may form. Avoid
contact with alkaline solutions which can lead to hydrolysis of Doxorubicin
hydrochloride injection.
Procedures
for Proper Handling and Disposal
Handle and dispose of
Doxorubicin hydrochloride injection consistent with recommendations for the
handling and disposal of hazardous drugs.1
Treat accidental contact with
the skin or eyes immediately by copious lavage with water, or soap and water,
or sodium bicarbonate solution. Do not abrade the skin by using a scrub brush.
Seek medical attention.
Dosage Forms and Strengths
Doxorubicin Hydrochloride
Injection, USP: Vials contain 10 mg/5 mL, 20 mg/10 mL, 50 mg/25 mL and 200
mg/100 mL Doxorubicin hydrochloride, USP as a clear red solution.
Contraindications
Doxorubicin hydrochloride is
contraindicated in patients with:
·
Severe myocardial
insufficiency [see Warnings
and Precautions (5.1)]
·
Recent (occurring within the
past 4 to 6 weeks) myocardial infarction [see Warnings
and Precautions (5.1)]
·
Severe persistent drug-induced
myelosuppression [see Warnings
and Precautions (5.4)]
·
Severe hepatic impairment
(defined as Child Pugh Class C or serum bilirubin level greater than 5
mg/dL) [see Warnings
and Precautions (5.5)]
· Severe hypersensitivity
reaction to Doxorubicin hydrochloride including anaphylaxis [see Adverse
Reactions (6.2)]
Warnings and Precautions
Cardiomyopathy
and Arrhythmias
Cardiomyopathy
Doxorubicin hydrochloride can
result in myocardial damage, including acute left ventricular failure. The risk
of cardiomyopathy is generally proportional to the cumulative exposure. Include
prior doses of other anthracyclines or anthracenediones in calculations of
total cumulative dosage for Doxorubicin hydrochloride. Cardiomyopathy may
develop during treatment or up to several years after completion of treatment
and can include decrease in LVEF and signs and symptoms of congestive heart
failure (CHF). The probability of developing cardiomyopathy is estimated to be
1 to 2% at a total cumulative dose of 300 mg/m2 of Doxorubicin
hydrochloride, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at a dose of 450
mg/m2, and
6 to 20% at a dose of 500 mg/m2, when Doxorubicin hydrochloride is administered every 3 weeks.
There is an additive or potentially synergistic increase in the risk of
cardiomyopathy in patients who have received radiotherapy to the mediastinum or
concomitant therapy with other known cardiotoxic agents such as
cyclophosphamide and trastuzumab.
Pericarditis and myocarditis
have also been reported during or following Doxorubicin hydrochloride
treatment.
Assess left ventricular
cardiac function (e.g., MUGA or echocardiogram) prior to initiation of
Doxorubicin hydrochloride, during treatment to detect acute changes, and after
treatment to detect delayed cardiotoxicity. Increase the frequency of
assessments as the cumulative dose exceeds 300 mg/m2. Use the same method of
assessment of LVEF at all time points [see Use in
Specific Populations (8.4)].
Consider the use of
dexrazoxane to reduce the incidence and severity of cardiomyopathy due to
Doxorubicin hydrochloride administration in patients who have received a
cumulative Doxorubicin hydrochloride dose of 300 mg/m2 and who will continue to
receive Doxorubicin hydrochloride.
Arrhythmias
Doxorubicin hydrochloride can
result in arrhythmias, including life-threatening arrhythmias, during or within
a few hours after Doxorubicin hydrochloride administration and at any time
point during treatment. Tachyarrhythmias, including sinus tachycardia,
premature ventricular contractions, and ventricular tachycardia, as well as
bradycardia may occur. Electrocardiographic changes including non-specific ST-T
wave changes, atrioventricular and bundle-branch block can also occur. These
electrocardiographic changes may be transient and self-limited and may not
require dose-modifications of Doxorubicin hydrochloride.
Secondary
Malignancies
The risk of developing
secondary acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS)
is increased following treatment with Doxorubicin hydrochloride. Cumulative
incidences ranged from 0.2% at five years to 1.5% at 10 years in two separate
trials involving the adjuvant treatment of women with breast cancer. These
leukemias generally occur within 1 to 3 years of treatment.
Extravasation
and Tissue Necrosis
Extravasation of Doxorubicin
hydrochloride can result in severe local tissue injury manifesting as
blistering, ulceration, and necrosis requiring wide excision of the affected
area and skin grafting. When given via a peripheral venous line, infuse
Doxorubicin over 10 minutes or less to minimize the risk of thrombosis or
perivenous extravasation. If signs or symptoms of extravasation occur,
immediately terminate the injection or infusion [see Dosage
and Administration (2.3)]. Extravasation may be present
in patients who do not experience a stinging or burning sensation or when blood
return is present on aspiration of the infusion needle. If extravasation is
suspected, apply ice to the site intermittently for 15 minutes, 4 times a day
for 3 days. If appropriate, administer dexrazoxane at the site of extravasation
as soon as possible and within the first 6 hours after extravasation.
Severe
Myelosuppression
Doxorubicin hydrochloride can
cause myelosuppression. In Study 1, the incidence of severe myelosuppression
was: grade 4 leukopenia (0.3%), grade 3 leukopenia (3%), and grade 4
thrombocytopenia (0.1%). A dose-dependent, reversible neutropenia is the
predominant manifestation of hematologic toxicity from Doxorubicin
hydrochloride. When Doxorubicin hydrochloride is administered every 21 days,
the neutrophil count reaches its nadir 10 to 14 days after administration with
recovery usually occurring by the 21st day.
Obtain baseline assessment of
blood counts and carefully monitor patients during treatment for possible
clinical complications due to myelosuppression.
Use in
Patients with Hepatic Impairment
The clearance of Doxorubicin
is decreased in patients with elevated serum bilirubin with an increased risk
of toxicity [see Use in
Specific Populations (8.7) and Clinical
Pharmacology (12.3)]. Reduce the dose of
Doxorubicin hydrochloride in patients with serum bilirubin levels of 1.2 to 5.0
mg/dL [see Dosage
and Administration (2.2)]. Doxorubicin is
contraindicated in patients with severe hepatic impairment (defined as Child
Pugh Class C or serum bilirubin level greater than 5 mg/dL) [see Contraindications
(4)]. Obtain liver tests including SGOT, SGPT, alkaline phosphatase,
and bilirubin prior to and during Doxorubicin hydrochloride therapy.
Tumor Lysis
Syndrome
Doxorubicin hydrochloride may
induce tumor lysis syndrome in patients with rapidly growing tumors. Evaluate
blood uric acid levels, potassium, calcium, phosphate, and creatinine after
initial treatment. Hydration, urine alkalinization, and prophylaxis with
allopurinol to prevent hyperuricemia may minimize potential complications of
tumor lysis syndrome.
Radiation
Sensitization and Radiation Recall
Doxorubicin hydrochloride can
increase radiation-induced toxicity to the myocardium, mucosa, skin, and liver.
Radiation recall, including but not limited to cutaneous and pulmonary
toxicity, can occur in patients who receive Doxorubicin hydrochloride after
prior radiation therapy.
Embryofetal
Toxicity
Doxorubicin hydrochloride can
cause fetal harm when administered to a pregnant woman. Doxorubicin
hydrochloride was teratogenic and embryotoxic in rats and rabbits at doses
lower than the recommended human dose.
If this drug is used during
pregnancy, or if the patient becomes pregnant while taking this drug, apprise
the patient of the potential hazard to a fetus [see Use in
Specific Populations (8.1)].
Advise female patients of
reproductive potential to use highly effective contraception during treatment
with Doxorubicin hydrochloride and for 6 months after treatment. Advise patients
to contact their healthcare provider if they become pregnant, or if pregnancy
is suspected, while taking Doxorubicin hydrochloride [see Use in
Specific Populations (8.1) and (8.6)].
Adverse Reactions
The following adverse
reactions are discussed in more detail in other sections of the labeling.
·
Cardiomyopathy and
Arrhythmias [see Warnings
and Precautions (5.1)]
·
Secondary Malignancies [see Warnings
and Precautions (5.2)]
·
Extravasation and Tissue
Necrosis [see Warnings
and Precautions (5.3)]
·
Severe Myelosuppression [see Warnings
and Precautions (5.4)]
·
Tumor Lysis Syndrome [see Warnings
and Precautions (5.6)]
· Radiation Sensitization and
Radiation Recall [see Warnings
and Precautions (5.7)]
Clinical
Trial Experience in Breast Cancer
Because clinical trials are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in
clinical practice.
The safety data below were
collected from 1492 women who received Doxorubicin hydrochloride at a dose of
60 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 (AC) every 3 weeks for 4
cycles for the adjuvant treatment of axillary lymph node positive breast
cancer. The median number of cycles received was 4. Selected adverse reactions
reported in this study are provided in Table 1. No treatment-related deaths
were reported in patients on either arm of the study.
.
Table 1. Selected Adverse Reactions in
Patients with Early Breast Cancer Involving Axillary Lymph Nodes
|
|
|
|
Conventional
|
|
|
AC*
|
CMF
|
|
|
N=1492
|
N=739
|
|
Adverse reactions, % of patients
|
|
|
|
Leukopenia
|
|
|
|
Grade 3 (1,000 to 1,999 /mm3)
|
3.4
|
9.4
|
|
Grade 4 (<1000 /mm3)
|
0.3
|
0.3
|
|
Thrombocytopenia
|
|
|
|
Grade 3 (25,000 to 49,999 /mm3)
|
0
|
0.3
|
|
Grade 4 (<25,000 /mm3)
|
0.1
|
0
|
|
Shock, sepsis
|
2
|
1
|
|
Systemic infection
|
2
|
1
|
|
Vomiting
|
|
|
|
Vomiting ≤12 hours
|
34
|
25
|
|
Vomiting >12 hours
|
37
|
12
|
|
Intractable
|
5
|
2
|
|
Alopecia
|
92
|
71
|
|
Cardiac dysfunction
|
|
|
|
Asymptomatic
|
0.2
|
0.1
|
|
Transient
|
0.1
|
0
|
|
Symptomatic
|
0.1
|
0
|
|
* Includes pooled data from patients who received
either AC alone for 4 cycles, or who were treated with AC for 4 cycles
followed by 3 cycles of CMF
|
Postmarketing
Experience
The following adverse
reactions have been identified during post-approval use of Doxorubicin
hydrochloride. 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.
Cardiac - cardiogenic shock
Cutaneous -Skin and nail hyperpigmentation, oncolysis, rash,
itching, photosensitivity, urticaria, acral erythema, palmar plantar
erythrodysesthesia
Gastrointestinal - Nausea, mucositis, stomatitis, necrotizing colitis,
typhlitis, gastric erosions, gastrointestinal tract bleeding, hematochezia,
esophagitis, anorexia, abdominal pain, dehydration, diarrhea, hyperpigmentation
of the oral mucosa
Hypersensitivity - Anaphylaxis
Laboratory
Abnormalities -Increased alanine
aminotransferase, increased aspartate aminotransferase
Neurological - Peripheral sensory and motor neuropathy, seizures, coma
Ocular - Conjunctivitis, keratitis, lacrimation
Vascular - Phlebosclerosis, phlebitis/thrombophlebitis, hot
flashes, thromboembolism
Other - Malaise/asthenia, fever, chills, weight gain
Drug Interactions
Effect of
CYP3A4 Inhibitors, Inducers and P-gp
Doxorubicin is a major
substrate of cytochrome P450 CYP3A4 and CYP2D6, and P-glycoprotein (P-gp).
Clinically significant interactions have been reported with inhibitors of
CYP3A4, CYP2D6, and/or P-gp (e.g., verapamil), resulting in increased
concentration and clinical effect of Doxorubicin. Inducers of CYP3A4 (e.g.,
phenobarbital, phenytoin, St. John’s Wort) and P-gp inducers may decrease the
concentration of Doxorubicin. Avoid concurrent use of Doxorubicin hydrochloride
with inhibitors and inducers of CYP3A4, CYP2D6, or P-gp.
Trastuzumab
Concurrent use of trastuzumab
and Doxorubicin hydrochloride results in an increased risk of cardiac
dysfunction. Avoid concurrent administration of Doxorubicin and trastuzumab.
The appropriate interval for administering Doxorubicin following trastuzumab
therapy has not been determined [see Warnings
and Precautions (5.1)].
Paclitaxel
Paclitaxel, when given prior
to Doxorubicin hydrochloride, increases the plasma-concentrations of
Doxorubicin and its metabolites. Administer Doxorubicin hydrochloride prior to
paclitaxel if used concomitantly.
Dexrazoxane
Do not administer dexrazoxane
as a cardioprotectant at the initiation of Doxorubicin hydrochloridecontaining
chemotherapy regimens. In a randomized trial in women with metastatic breast
cancer, initiation of dexrazoxane with Doxorubicin hydrochloride-based
chemotherapy resulted in a significantly lower tumor response rate (48% vs.
63%; p=0.007) and shorter time to progression than in women who received
Doxorubicin hydrochloride-based chemotherapy alone.
6-Mercaptopurine
Doxorubicin hydrochloride may
potentiate 6-mercaptopurine-induced hepatotoxicity. In 11 patients with
refractory leukemia treated with 6-mercaptopurine (500 mg/m2 intravenously daily for
5 days per cycle every 2 to 3 weeks) and Doxorubicin hydrochloride (50 mg/m2 intravenous once per
cycle every 2 to 3 weeks) alone or with vincristine and prednisone, all
developed hepatic dysfunction manifested by elevations of total serum
bilirubin, alkaline phosphatase and aspartate aminotransferase.
USE IN SPECIFIC POPULATIONS
Pregnancy
Teratogenic
Effects: Pregnancy Category D
Risk
Summary
Doxorubicin hydrochloride can
cause fetal harm when administered to a pregnant woman. Doxorubicin
hydrochloride was teratogenic and embryotoxic in rats and rabbits at doses
approximately 0.07 times (based on body surface area) the recommended human
dose of 60 mg/m2. If this drug is used during pregnancy, or if the patient
becomes pregnant while taking this drug, apprise the patient of the potential
hazard to a fetus.
Animal
Data
Doxorubicin hydrochloride was
teratogenic and embryotoxic at doses of 0.8 mg/kg/day (about 0.07 times the
recommended human dose based on body surface area) when administered during the
period of organogenesis in rats. Teratogenicity and embryotoxicity were also
seen using discrete periods of treatment. The most susceptible was the 6- to
9-day gestation period at doses of 1.25 mg/kg/day and greater. Characteristic
malformations included esophageal and intestinal atresia, tracheo-esophageal
fistula, hypoplasia of the urinary bladder, and cardiovascular anomalies.
Doxorubicin hydrochloride was embryotoxic (increase in embryofetal deaths) and
abortifacient at 0.4 mg/kg/day (about 0.07 times the recommended human dose
based on body surface area) in rabbits when administered during the period of
organogenesis.
Nursing
Mothers
Doxorubicin has been detected
in the milk of at least one lactating patient [see Clinical
Pharmacology (12.3)]. Because of the potential for
serious adverse reactions in nursing infants from Doxorubicin hydrochloride, a
decision should be made whether to discontinue nursing or discontinue the drug,
taking into account the importance of the drug to the mother.
Pediatric Use
Based on postmarketing
reports, pediatric patients treated with Doxorubicin hydrochloride are at risk
for developing late cardiovascular dysfunction. Risk factors include young age
at treatment (especially less than 5 years), high cumulative doses and receipt
of combined modality therapy. Long-term periodic cardiovascular monitoring is
recommended for all pediatric patients who have received Doxorubicin hydrochloride.
Doxorubicin hydrochloride, as a component of intensive chemotherapy regimens
administered to pediatric patients, may contribute to prepubertal growth
failure and may also contribute to gonadal impairment, which is usually
temporary.
There are no recommended dose
adjustments based on age. Doxorubicin clearance was increased in patients aged
2 years to 20 years as compared to adults, while Doxorubicin clearance was
similar in children less than 2 years as compared to adults [see Clinical
Pharmacology (12.3)].
Geriatric Use
Clinical experience in
patients who were 65 years of age and older who received Doxorubicin
hydrochloride-based chemotherapy regimens for metastatic breast cancer showed
no overall differences in safety and effectiveness compared with younger
patients.
Females and
Males of Reproductive Potential
Contraception
Females
Doxorubicin hydrochloride can
cause fetal harm when administered during pregnancy. Advise female patients of
reproductive potential to use highly effective contraception during treatment
with Doxorubicin hydrochloride and for 6 months after treatment. Advise
patients to contact their healthcare provider if they become pregnant, or if
pregnancy is suspected, while taking Doxorubicin hydrochloride [see Use in
Specific Populations (8.1)].
Males
Doxorubicin hydrochloride may
damage spermatozoa and testicular tissue, resulting in possible genetic fetal
abnormalities. Males with female sexual partners of reproductive potential
should use effective contraception during and for 6 months after
treatment [see Nonclinical
Toxicology (13.1)].
Infertility
Females
In females of reproductive
potential, Doxorubicin hydrochloride may cause infertility and result in
amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is
related to age at treatment [see Nonclinical
Toxicology (13.1)].
Males
Doxorubicin hydrochloride may
result in oligospermia, azoospermia, and permanent loss of fertility. Sperm
counts have been reported to return to normal levels in some men. This may
occur several years after the end of therapy.
Hepatic
Impairment
The clearance of Doxorubicin
was reduced in patients with elevated serum bilirubin levels. Reduce the dose
of Doxorubicin hydrochloride in patients with serum bilirubin levels greater
than 1.2 mg/dL [See Dosage
and Administration (2.2) and Warnings
and Precautions (5.5)].
Doxorubicin hydrochloride is
contraindicated in patients with severe hepatic impairment (defined as Child
Pugh Class C or serum bilirubin levels greater than 5 mg/dL) [see Contraindications
(4)].
Overdosage
Few cases of overdose have
been described. A 58-year-old man with acute lymphoblastic leukemia received
10-fold overdose of Doxorubicin hydrochloride (300 mg/m2) in one day. He was treated
with charcoal filtration, hemopoietic growth factor (G-CSF), proton pump
inhibitor and antimicrobial prophylaxis. The patient suffered sinus
tachycardia, grade 4 neutropenia and thrombocytopenia for 11 days, severe
mucositis and sepsis. The patient recovered completely 26 days after the
overdose. A 17-year-old girl with osteogenic sarcoma received 150 mg of
Doxorubicin hydrochloride daily for 2 days (intended dose was 50 mg per day for
3 days). The patient developed severe mucositis on days 4 to 7 after the
overdose and chills and pyrexia on day 7. The patient was treated with
antibiotics and platelets and recovered 18 days after overdose.
Doxorubicin Description
Doxorubicin hydrochloride, USP
is a cytotoxic, anthracycline, topoisomerase II inhibitor isolated from
cultures of Streptomyces peucetius var. caesius. Chemically, Doxorubicin hydrochloride, USP
is: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10
tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S-cis)-. The molecular weight of Doxorubicin hydrochloride,
USP is 579.99, and the molecular formula is C27H29NO11•HCl.The chemical structure of
Doxorubicin hydrochloride, USP is:
Doxorubicin hydrochloride
injection, USP is a clear, red, sterile, isotonic aqueous solution provided in
vials containing 10 mg/5 mL, 20 mg/10 mL, 50 mg/25 mL or 200 mg/100 mL of
Doxorubicin hydrochloride, USP. The drug product has demonstrated inherent
antimicrobial activity suitable for a multiple dose presentation. Each
milliliter of solution contains 2 mg of Doxorubicin hydrochloride, USP.
Inactive ingredients include sodium chloride 0.9%, USP, and water for
injection, USP, quantity sufficient. The pH of the solution is adjusted to 3.0
with hydrochloric acid, USP.
Doxorubicin - Clinical Pharmacology
Mechanism of
Action
The cytotoxic effect of
Doxorubicin hydrochloride 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 hydrochloride cytocidal activity.
Pharmacokinetics
Pharmacokinetic studies
conducted in patients with various types of tumors have shown that Doxorubicin
follows multiphasic disposition after intravenous injection. The distribution
half-life is approximately 5 minutes, while the terminal half-life is 20 to 48
hours. In four patients, Doxorubicin demonstrated dose-independent
pharmacokinetics across a dose range of 30 to 70 mg/m2.
Distribution
Steady-state distribution
volume ranges from 809 to 1214 L/m2. Binding of Doxorubicin and its major metabolite,
Doxorubicinol, to plasma proteins is about 75% and is independent of plasma
concentration of Doxorubicin up to 1.1 mcg/mL.
Doxorubicin was measured in
the milk of one lactating patient after therapy with 70 mg/m2 of Doxorubicin
hydrochloride given as a 15-minute intravenous infusion. The peak milk
concentration at 24 hours after treatment was 4.4-fold greater than the
corresponding plasma concentration. Doxorubicin was detectable in the milk up
to 72 hours.
Doxorubicin does not cross the
blood brain barrier.
Metabolism
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 hydrochloride.
Disposition of Doxorubicinol in patients is formation rate limited, with the
terminal half-life of Doxorubicinol being similar to Doxorubicin. The relative
exposure of Doxorubicinol, i.e., the ratio between the AUC of Doxorubicinol and
the AUC of Doxorubicin is approximately 0.5.
Excretion
Plasma clearance is in the
range 324 to 809 mL/min/m2 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. In urine, less than 3% of the dose was recovered as Doxorubicinol over
7 days.
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.
Pediatric
patients
Following administration of
doses ranging from 10 to 75 mg/m2 of Doxorubicin hydrochloride to 60 children and
adolescents ranging from 2 months to 20 years of age, Doxorubicin clearance
averaged 1443 ± 114 mL/min/m2. Further analysis demonstrated that clearance in 52 children
greater than 2 years of age (1540 mL/min/m2) was increased compared with
adults. However, clearance in infants younger than 2 years of age (813 mL/min/m2) was decreased compared with
older children and approached the range of clearance values determined in
adults [see Use in
Specific Populations (8.4)].
Patient
Gender
There is no recommended dose
adjustment based on gender. A published clinical study involving 6 men and 21
women with no prior anthracycline therapy reported a significantly higher
median Doxorubicin clearance in men compared to women (1088 mL/min/m2 versus 433 mL/min/m2). However, the terminal
half-life of Doxorubicin was longer in men compared to women (54 versus 35
hours).
Patients
with hepatic impairment
The clearance of Doxorubicin
and Doxorubicinol was reduced in patients with elevation in serum
bilirubin [see Dosage
and Administration (2.2) and Warnings
and Precautions (5.5)].
Nonclinical Toxicology
Carcinogenesis
and Mutagenesis and Impairment of Fertility
Doxorubicin hydrochloride
treatment results in an increased risk of secondary malignancies based on
postmarketing reports [see Warnings
and Precautions (5.2)]. Doxorubicin hydrochloride
was mutagenic in the in vitro Ames
assay, and clastogenic in multiple in vitro assays
(CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay.
Doxorubicin hydrochloride
decreased fertility in female rats at the doses of 0.05 and 0.2 mg/kg/day
(approximately 0.005 and 0.02 times the recommended human dose, based on body
surface area).
A single intravenous dose of
0.1 mg/kg Doxorubicin hydrochloride (approximately 0.01 times the recommended
human dose based on body surface area) was toxic to male reproductive organs in
animal studies, producing testicular atrophy, diffuse degeneration of the
seminiferous tubules, and oligospermia/hypospermia in rats. Doxorubicin
hydrochloride induces DNA damage in rabbit spermatozoa and dominant lethal
mutations in mice.
Clinical Studies
The clinical efficacy of
Doxorubicin hydrochloride-containing regimens for the post-operative, adjuvant
treatment of surgically resected breast cancer was evaluated in a meta-analysis
conducted by the Early Breast Cancer Trialists Collaborative Group (EBCTCG).
The EBCTCG meta-analyses compared cyclophosphamide, methotrexate, and
5-fluorouracil (CMF) to no chemotherapy (19 trials including 7523 patients) and
Doxorubicin hydrochloride-containing regimens with CMF as an active control (6
trials including 3510 patients). Data from the meta-analysis of trials
comparing CMF to no therapy were used to establish the historical treatment
effect size for CMF regimens. The major efficacy outcome measures were
disease-free survival (DFS) and overall survival (OS).
Of the 3510 women (2157
received Doxorubicin hydrochloride-containing regimens and 1353 received CMF
treatment) with early breast cancer involving axillary lymph nodes included in
the six trials from the meta-analyses, approximately 70% were premenopausal and
30% were postmenopausal. At the time of the meta-analysis, 1745 first
recurrences and 1348 deaths had occurred. The analyses demonstrated that
Doxorubicin hydrochloride-containing regimens retained at least 75% of the
historical CMF adjuvant effect on DFS with a hazard ratio (HR) of 0.91 (95% CI,
0.82 to 1.01) and on OS with a HR of 0.91 (95% CI, 0.81 to 1.03). Results of
these analyses for both DFS and OS are provided in Table 2 and Figures 1 and 2.
Table 2. Summary of Randomized Trials
Comparing Doxorubicin Hydrochloride-Containing Regimens Versus CMF in EBCTCG
Meta-Analysis
|
|
|
Regimens
|
No. of Cycles
|
No. of
|
Doxorubicin Hydrochloride-Containing
|
|
Study
|
|
|
|
Regimens vs CMF
|
|
(starting year)
|
|
|
Patients
|
HR** (95% CI)
|
|
|
|
|
|
DFS
|
OS
|
|
NSABP B-15 (1984)
|
AC
|
4
|
1562*
|
|
|
|
|
|
|
|
0.93 (0.82 to
1.06)
|
0.97 (0.83 to
1.12)
|
|
|
CMF
|
6
|
776
|
|
|
|
SECSG 2 (1976)
|
FAC
|
6
|
260
|
|
|
|
|
|
|
|
0.86 (0.66 to
1.13)
|
0.93 (0.69 to
1.26)
|
|
|
CMF
|
6
|
268
|
|
|
|
ONCOFRANCE (1978)
|
FACV
|
12
|
138
|
|
|
|
|
|
|
|
0.71 (0.49 to
1.03)
|
0.65 (0.44 to
0.96)
|
|
|
CMF
|
12
|
113
|
|
|
|
SE Sweden
|
AC
|
6
|
21
|
|
|
|
BCG A (1980)
|
|
|
|
0.59 (0.22 to
1.61)
|
0.53 (0.21 to
1.37)
|
|
|
CMF
|
6
|
22
|
|
|
|
NSABC Israel
|
AVbCMF †
|
4
|
55
|
|
|
|
Br0283 (1983)
|
|
6
|
|
0.91 (0.53 to
1.57)
|
0.88 (0.47 to
1.63)
|
|
|
CMF
|
8
|
50
|
|
|
|
Austrian BCSG 3 (1984)
|
CMFVA
|
6
|
21
|
|
|
|
|
|
|
|
1.07 (0.73 to
1.55)
|
0.93 (0.64 to
1.35)
|
|
|
CMF
|
8
|
22
|
|
|
|
|
Doxorubicin hydrochloride -
|
2157
|
|
|
|
Combined Studies
|
Containing Regimens
|
|
0.91 (0.82 to 1.01)
|
0.91 (0.81 to 1.03)
|
|
|
CMF
|
1353
|
|
|
|
Abbreviations: DFS=disease free survival;
OS=overall survival; AC=Doxorubicin hydrochloride, cyclophosphamide;
AVbCMF=Doxorubicin hydrochloride, vinblastine, cyclophosphamide,
methotrexate, 5-fluorouracil; CMF=cyclophosphamide, methotrexate,
5-fluorouracil; CMFVA=cyclophosphamide, methotrexate, 5-fluorouracil,
vincristine, Doxorubicin hydrochloride; FAC=5-fluorouracil, Doxorubicin
hydrochloride, cyclophosphamide; FACV=5-fluorouracil, Doxorubicin
hydrochloride, cyclophosphamide, vincristine; HR=hazard ratio; CI=confidence
interval
|
|
*Includes pooled data from patients who received
either AC alone for 4 cycles, or who were treated with AC for 4 cycles
followed by 3 cycles of CMF.
|
|
** a hazard ratio of less than 1 indicates that the
treatment with Doxorubicin hydrochloride-containing regimens is associated
with lower risk of disease recurrences or death compared to the treatment
with CMF.
|
|
† Patients received alternating cycles of AVb
and CMF.
|
Figure 1. Meta-analysis of Disease-Free Survival
Figure 2. Meta-analysis of Overall Survival
REFERENCES
1.
“Hazardous Drugs”. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
2.
How is Doxorubicin Supplied
Doxorubicin hydrochloride
injection, USP is supplied in single-dose, flip-top vials, as a clear, red
solution containing Doxorubicin hydrochloride, USP 2 mg/mL in the following
package strengths:
NDC
45963-733-55: 10 mg in 5 mL Single
Dose Vial
NDC
45963-733-57: 20 mg in 10 mL; Single
Dose Vial
NDC
45963-733-68: 50 mg in 25 mL; Single
Dose Vial
NDC
45963-733-60: 200 mg in 100 mL;
Multiple Dose Vial
For
the single dose vials: Store under
refrigeration between 2° to 8°C (36° to 46°F).
Protect
from light. Retain in carton until
time of use. Discard unused portion.
For
the multiple dose vial: Store under
refrigeration between 2° to 8°C (36° to 46°F).
Protect
from light. Retain in carton until
contents are used.
Storage of Doxorubicin
hydrochloride injection, USP under refrigerated conditions can result in the
formation of a gelled product. Place gelled product at room temperature [15º to
30ºC (59º to 86ºF)] for 2 to 4 hours to return the product to a slightly
viscous, mobile solution.
Handling
and Disposal
Handle and dispose of
Doxorubicin hydrochloride injection, USP consistent with recommendations for
the handling and disposal of hazardous drugs.1
Sterile,
Nonpyrogenic, Preservative-free.
The
vial stopper is not made with natural rubber latex.
Patient Counseling Information
See FDA-Approved Patient
Labeling (Patient Information).
Inform patients of the
following:
·
Doxorubicin hydrochloride
injection can cause irreversible myocardial damage. Advise patients to contact
a healthcare provider for symptoms of heart failure during or after treatment
with Doxorubicin hydrochloride injection [see Warnings
and Precautions (5.1)].
·
There is an increased risk of
treatment-related leukemia from Doxorubicin hydrochloride injection [see Warnings
and Precautions (5.2)].
·
Doxorubicin hydrochloride
injection can reduce the absolute neutrophil count resulting in an increased
risk of infection. Advise patients to contact a healthcare provider for new
onset fever or symptoms of infection [see Warnings
and Precautions (5.4)].
·
Doxorubicin hydrochloride
injection can cause fetal harm when administered during pregnancy. Advise females
of reproductive potential to use effective contraception during treatment with
Doxorubicin hydrochloride injection and for 6 months after treatment, and to
contact their healthcare provider if they become pregnant, or if pregnancy is
suspected, during treatment with Doxorubicin hydrochloride injection [see Warnings
and Precautions (5.8) and Use in
Specific Populations (8.6)].
·
Doxorubicin hydrochloride
injection may induce chromosomal damage in sperm, which may lead to loss of
fertility and offspring with birth defects. Advise patients to use effective
contraception during and for 6 months after treatment [see Warnings
and Precautions (5.8) and Use in
Specific Populations (8.6)].
·
Doxorubicin hydrochloride
injection can cause premature menopause in females and loss of fertility in
males [see Use in
Specific Populations (8.6)].
·
Discontinue nursing while
receiving Doxorubicin hydrochloride injection [see Use in
Specific Populations (8.3)].
·
Doxorubicin hydrochloride
injection can cause nausea, vomiting, diarrhea, mouth/oral pain and sores.
·
Advise patients to contact a
healthcare provider should they develop any severe symptoms that prevent them
from eating and drinking [see Adverse
Reactions (6)].
·
Doxorubicin hydrochloride
injection causes alopecia [see Adverse
Reactions (6.1)].
·
Doxorubicin hydrochloride
injection can cause their urine to appear red for 1 to 2 days after
administration.
Made
in Italy
Distributed
by:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA
Revised – March 2015
PATIENT INFORMATION
Doxorubicin
Hydrochloride (dox-oh-ROO-bih-sin HYE-droe-KLOR-ide)
Injection, USP
Rx
Only
What
is the most important information I should know about Doxorubicin hydrochloride
injection?
Doxorubicin
hydrochloridemay cause serious side effects including:
Heart failure. Doxorubicin
hydrochloride may cause heart muscle damage that may lead to heart
failure, which is a condition in which the heart does not pump well. Heart
failure is irreversible in some cases and can lead to death. Heart failure
can happen during your treatment with Doxorubicin hydrochloride or months
to years after stopping treatment. Your risk of heart muscle damage
increases with higher total amounts of Doxorubicin hydrochloride that you
receive in your lifetime. Your risk of heart failure is higher if you:
o already have other heart problems
o have had or are currently receiving radiation therapy to your
chest
o have had treatment with certain other anti-cancer medicines
o take other medicines that can have severe side effects on your
heart
Tell your doctor if you get
any of these symptoms of heart failure during or after treatment with
Doxorubicin
hydrochloride:
|
• extreme tiredness or weakness
|
• fast heartbeat
|
|
• shortness of breath
|
• swelling of your feet and ankles
|
Your doctor will do tests to
check the strength of your heart muscle before, during, and after your
treatment with Doxorubicin hydrochloride.
· Risk
of new cancers. You may have an
increased risk of developing certain blood cancers called acute myelogenous
leukemia (AML) or myelodysplastic syndrome (MDS) after treatment with
Doxorubicin hydrochloride. Talk with your doctor about your risk of developing
new cancers if you take Doxorubicin hydrochloride.
· Skin
damage near the vein where Doxorubicin hydrochlorideis given (Injection site
reaction).Doxorubicin hydrochloride can damage the
skin if it leaks out of the vein. Symptoms of infusion reaction include
blisters and skin sores at injection site which may require skin grafts.
· Decreased
blood cell counts. Doxorubicin
hydrochloride can cause a decrease in neutrophils (a type of white blood cells
important in fighting bacterial infections) and platelets (important for
clotting and to control bleeding). This may lead to a serious infection, the
need for blood transfusions, treatment in a hospital and death. Your doctor
will check your blood cell count during your treatment with Doxorubicin
hydrochloride and after you have stopped your treatment. Call your doctor right
away if you get a fever (temperature of 100.4ºF or greater) or chills with
shivering.
What
is Doxorubicin hydrochloride injection?
Doxorubicin hydrochloride is a
prescription medicine used to treat certain types of cancers. Doxorubicin
hydrochloride may be used alone or along with other anti-cancer medicines.
Who
should not receive Doxorubicin hydrochloride injection?
Do not
receive Doxorubicin hydrochlorideif:
·
you have had a recent heart
attack or have severe heart problems
·
your blood cell counts
(platelets, red blood cells, and white blood cells) are very low because of
prior chemotherapy
·
you have a severe liver
problem
·
you have had a serious
allergic reaction to Doxorubicin hydrochloride
What should I tell my doctor before receiving Doxorubicin
hydrochloride injection?
Before
you receive Doxorubicin hydrochloride, tell your doctor if you:
·
have heart problems including
heart failure
·
are currently receiving
radiation therapy or plan to receive radiation to the chest
·
have severe liver problems
·
have had an allergic reaction
to Doxorubicin hydrochloride
·
have any other medical
conditions
·
are pregnant or plan to become
pregnant. Doxorubicin hydrochloride can harm your unborn baby. Women who are
able to become pregnant and men who take Doxorubicin hydrochloride should use
effective birth control (contraception) during treatment and for 6 months after
treatment. Talk to your doctor about birth control methods. If you or your
partner becomes pregnant, tell your doctor right away.
·
are breastfeeding or plan to
breast feed. Doxorubicin hydrochloride can pass into your breast milk and harm
your baby. You and your doctor should decide if you will receive Doxorubicin
hydrochloride or breastfeed. You should not do both.
Tell
your doctor about all the medicines you take, including prescription and over-the-counter medicines,
vitamins, and herbal supplements. Doxorubicin hydrochloride can interact with
other medicines. Do not start any new medicine before you talk with the doctor
that prescribed Doxorubicin hydrochloride.
Know the medicines you take.
Keep a list to show your doctor and pharmacist each time you get a new
medicine.
How
will I receive Doxorubicin hydrochloride injection?
·
Doxorubicin hydrochloride will
be given to you into your vein.
What
are the possible side effects of Doxorubicin hydrochloride injection?
Doxorubicin
hydrochloridemay cause serious side effects, including:
·
See “What
is the most important information I should know about Doxorubicin hydrochloride
injection?”
Doxorubicin
hydrochloride may cause lower sperm counts and sperm problems in men.
This could affect your ability
to father a child and cause birth defects. Talk to your healthcare provider if
this is a concern for you. Talk to your healthcare provider about family
planning options that might be right for you.
Irreversible
amenorrhea or early menopause. Your
periods (menstrual cycle) may completely stop when you receive Doxorubicin
hydrochloride. Your periods may or may not return following treatment. Talk to
your healthcare provider about family planning options that might be right for
you.
The
most common side effects of Doxorubicin hydrochloride include:
·
Total hair loss (alopecia).
Your hair may re-grow after your treatment.
·
nausea
·
vomiting
Other
side effects:
·
Red colored urine. You may
have red colored urine for 1 to 2 days after your infusion of Doxorubicin
hydrochloride. This is normal. Tell your doctor if it does not stop in a few
days, or if you see what looks like blood or blood clots in your urine.
·
Darkening of your nails or
separation of your nails from your nail bed.
·
Easy bruising or bleeding.
·
Call your doctor if you have
severe symptoms that prevent you from eating or drinking, such as:
o nausea
o vomiting
o diarrhea
o mouth sores
Tell your doctor or nurse if
you have any side effect that bothers you or that does not go away.
These are not all of the
possible side effects of Doxorubicin hydrochloride.
Call
your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
General
information about the safe and effective use of Doxorubicin hydrochloride
injection.
Medicines are sometimes
prescribed for purposes other than those listed in a Patient Information
leaflet.
You can ask your pharmacist or
doctor for information about Doxorubicin hydrochloride that is written for
health professionals.
For more information, call
Actavis at 1-800-432-8534.
What
are the ingredients of Doxorubicin hydrochloride injection, USP?
Active
ingredient: Doxorubicin
hydrochloride, USP
Inactive
ingredients: 0.9% sodium chloride,
USP, water for injection, USP, and hydrochloric acid, USP.
This Patient Information has
been approved by the U.S. Food and Drug Administration.
Made
in Italy
Distributed
by:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA
Revised – March 2015
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
|
Doxorubicin HYDROCHLORIDE Doxorubicin
hydrochloride injection, solution
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:45963-733
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active Ingredient/Active
Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
Doxorubicin HYDROCHLORIDE (Doxorubicin)
|
Doxorubicin
HYDROCHLORIDE
|
2 mg
in 1 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
SODIUM CHLORIDE
|
|
|
WATER
|
|
|
|
Product
Characteristics
|
|
Color
|
RED (CLEAR)
|
Score
|
|
|
Shape
|
|
Size
|
|
|
Flavor
|
|
Imprint Code
|
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:45963-733-55
|
1 VIAL,
SINGLE-DOSE in 1 CARTON
|
|
|
1
|
|
5 mL in 1 VIAL,
SINGLE-DOSE
|
|
|
2
|
NDC:45963-733-57
|
1 VIAL,
SINGLE-DOSE in 1 CARTON
|
|
|
2
|
|
10 mL in 1
VIAL, SINGLE-DOSE
|
|
|
3
|
NDC:45963-733-68
|
1 VIAL,
SINGLE-DOSE in 1 CARTON
|
|
|
3
|
|
25 mL in 1
VIAL, SINGLE-DOSE
|
|
|
4
|
NDC:45963-733-60
|
1 VIAL,
MULTI-DOSE in 1 CARTON
|
|
|
4
|
|
100 mL in 1
VIAL, MULTI-DOSE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
ANDA
|
ANDA203622
|
11/01/2014
|
|
|
|
Labeler - Actavis Pharma, Inc. (119723554)
|
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Actavis Italy
Spa A Socio Unico
|
|
857007913
|
ANALYSIS(45963-733),
LABEL(45963-733), MANUFACTURE(45963-733), PACK(45963-733)
|
Revised:
03/2015
Actavis Pharma, Inc.
