PROLIA- denosumab injection

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

DENOSUMAB (UNII: 4EQZ6YO2HI) (DENOSUMAB - UNII:4EQZ6YO2HI)

Available from:

Amgen Inc

INN (International Name):

DENOSUMAB

Composition:

DENOSUMAB 60 mg in 1 mL

Administration route:

SUBCUTANEOUS

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Prolia is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, Prolia reduces the incidence of vertebral, nonvertebral, and hip fractures [see Clinical Studies (14.1)] . Prolia is indicated for treatment to increase bone mass in men with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy [see Clinical Studies (14.2)] . Prolia is indicated for the treatment of glucocorticoid-induced osteoporosis in men and women at high risk of fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least 6 months. High risk of fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy [see Clinical Studies (14.3)] . Prolia is indicated as a treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer. In these patients Prolia also reduced the incidence of vertebral fractures [see Clinical Studies (14.4)] . Prolia is indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer [see Clinical Studies (14.5)] . Prolia is contraindicated in: - Patients with hypocalcemia: Pre-existing hypocalcemia must be corrected prior to initiating therapy with Prolia [see Warnings and Precautions (5.1)] . - Pregnant women: Prolia may cause fetal harm when administered to a pregnant woman. In women of reproductive potential, pregnancy testing should be performed prior to initiating treatment with Prolia [see Use in Specific Populations (8.1)] . - Patients with hypersensitivity to Prolia: Prolia is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. Reactions have included anaphylaxis, facial swelling, and urticaria [see Warnings and Precautions (5.3), Adverse Reactions (6.2)] . Risk Summary Prolia is contraindicated for use in pregnant women because it may cause harm to a fetus. There are insufficient data with denosumab use in pregnant women to inform any drug-associated risks for adverse developmental outcomes. In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes, abnormal bone growth, and decreased neonatal growth [see Data] . Data Animal Data The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a "knockout mouse"). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy starting at gestational day 20 and at a pharmacologically active dose 50-fold higher than the recommended human dose based on body weight, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia, and tooth malalignment; and decreased neonatal growth. At birth out to 1 month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero ; however, development and lactation have not been fully evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation [see Use in Specific Populations (8.2), Nonclinical Toxicology (13.2)] . The no effect dose for denosumab-induced teratogenicity is unknown. However, a Cmax of 22.9 ng/mL was identified in cynomolgus monkeys as a level in which no biologic effects (NOEL) of denosumab were observed (no inhibition of RANKL) [see Clinical Pharmacology (12.3)] . Risk Summary There is no information regarding the presence of denosumab in human milk, the effects on the breastfed infant, or the effects on milk production. Denosumab was detected in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio) and maternal mammary gland development was normal, with no impaired lactation. However, pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.2)] . Based on findings in animals, Prolia can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Prolia treatment. Contraception Females Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of Prolia. Males Denosumab was present at low concentrations (approximately 2% of serum exposure) in the seminal fluid of male subjects given Prolia. Following vaginal intercourse, the maximum amount of denosumab delivered to a female partner would result in exposures approximately 11000 times lower than the prescribed 60 mg subcutaneous dose, and at least 38 times lower than the NOEL in monkeys. Therefore, male condom use would not be necessary as it is unlikely that a female partner or fetus would be exposed to pharmacologically relevant concentrations of denosumab via seminal fluid [see Clinical Pharmacology (12.3)] . The safety and effectiveness of Prolia have not been established in pediatric patients. In one multicenter, open-label study conducted in 153 pediatric patients with osteogenesis imperfecta, aged 2 to 17 years, evaluating fracture risk reduction, efficacy was not established. Hypercalcemia has been reported in pediatric patients with osteogenesis imperfecta treated with denosumab products, including Prolia. Some cases required hospitalization and were complicated by acute renal injury [see Warnings and Precautions (5.11)]. Clinical studies in pediatric patients with osteogenesis imperfecta were terminated early due to the occurrence of life-threatening events and hospitalizations due to hypercalcemia. Based on results from animal studies, Prolia may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years. Juvenile Animal Toxicity Data Treatment with Prolia may impair long-bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Prolia therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 10 and 50 times (10 and 50 mg/kg dose) higher than the recommended human dose of 60 mg administered every 6 months, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab [see Nonclinical Toxicology (13.2)]. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes, reduced hematopoiesis, tooth malalignment, and decreased neonatal growth. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary, and inguinal lymph nodes remained absent 6 months post-birth [see Use in Specific Populations (8.1)] . Of the total number of patients in clinical studies of Prolia, 9943 patients (76%) were ≥ 65 years old, while 3576 (27%) were ≥ 75 years old. Of the patients in the osteoporosis study in men, 133 patients (55%) were ≥ 65 years old, while 39 patients (16%) were ≥ 75 years old. Of the patients in the glucocorticoid-induced osteoporosis study, 355 patients (47%) were ≥ 65 years old, while 132 patients (17%) were ≥ 75 years old. No overall differences in safety or efficacy were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is necessary in patients with renal impairment. Severe hypocalcemia resulting in hospitalization, life-threatening events and fatal cases have been reported postmarketing. In clinical studies, patients with advanced chronic kidney disease (i.e., eGFR < 30 mL/min/1.73 m2 ), including dialysis-dependent patients, were at greater risk of developing hypocalcemia. The presence of underlying chronic kidney disease-mineral bone disorder (CKD-MBD, renal osteodystrophy) markedly increases the risk of hypocalcemia. Concomitant use of calcimimetic drugs may also worsen hypocalcemia risk. Consider the benefits and risks to the patient when administering Prolia to patients with advanced chronic kidney disease. Monitor calcium and mineral levels (phosphorus and magnesium). Adequate intake of calcium and vitamin D is important in patients with advanced chronic kidney disease including dialysis-dependent patients [see Dosage and Administration (2.2),Warnings and Precautions (5.1), Adverse Reactions (6.1) and Clinical Pharmacology (12.3)] .

Product summary:

How Supplied Prolia injection is a clear, colorless to pale yellow solution supplied in a single-dose prefilled syringe with a safety guard. The prefilled syringe is not made with natural rubber latex. Storage and Handling Store Prolia in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Prior to administration, Prolia may be allowed to reach room temperature (up to 25°C/77°F) in the original container. Once removed from the refrigerator, Prolia must not be exposed to temperatures above 25°C/77°F and must be used within 14 days. If not used within the 14 days, Prolia should be discarded. Do not use Prolia after the expiry date printed on the label. Protect Prolia from direct light and heat. Avoid vigorous shaking of Prolia.

Authorization status:

Biologic Licensing Application

Patient Information leaflet

Amgen Inc
----------
This Medication
Guide has been
approved by the U.S.
Food and Drug
Administration.
Revised: 01/2024
Medication Guide
Prolia® (PRÓ-lee-a)
(denosumab)
Injection, for subcutaneous use
What is the most important information I
should know about Prolia?
If you receive Prolia, you should not
receive XGEVA®. Prolia contains the
same medicine as Xgeva (denosumab).
Prolia can cause serious side effects
including:
•
Increased risk of severe low
calcium levels in your blood
(hypocalcemia). Prolia may lower
the calcium levels in your blood.
If you have low blood calcium
before you start receiving Prolia,
it may get worse during
treatment. Your low blood
calcium must be treated before
you receive Prolia. Talk to your
doctor before starting Prolia.
Your doctor may prescribe
calcium and vitamin D to help
prevent low calcium levels in
your blood while you take Prolia.
Take calcium and vitamin D as
your doctor tells you to.
If you have advanced chronic
kidney disease (may or may not
be on kidney dialysis), Prolia may
increase your risk for severe low
calcium levels in your blood,
which could result in
hospitalization, life-threatening
events and death. A mineral and
bone disorder associated with
kidney disease called chronic
kidney disease-mineral bone
disorder (CKD-MBD) may
increase your risk for severe low
calcium levels in blood. Before
you start Prolia and during
treatment, your doctor may need
to do certain blood tests to check
for CKD-MBD.
Most people with low blood
calcium levels do not have
symptoms, but some people may
have symptoms. Call your doctor
right away if you have symptoms
of low blood calcium such as:
•
spasms, twitches, or
cramps in your muscles
•
numbness or tingling in
your fingers, toes, or
around your mouth
•
Serious allergic reactions. Serious
allergic reactions have happened
in people who take Prolia. Call
your doctor or go to your nearest
emergency room right away if
you have any symptoms of a
serious allergic reaction.
Symptoms of a serious allergic
reaction may include:
�

Summary of Product characteristics

PROLIA- DENOSUMAB INJECTION
AMGEN INC
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
PROLIA SAFELY AND
EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR PROLIA.
PROLIA (DENOSUMAB) INJECTION, FOR SUBCUTANEOUS USE
INITIAL U.S. APPROVAL: 2010
WARNING: SEVERE HYPOCALCEMIA IN PATIENTS WITH ADVANCED KIDNEY DISEASE
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
PATIENTS WITH ADVANCED CHRONIC KIDNEY DISEASE ARE AT GREATER RISK OF
SEVERE
HYPOCALCEMIA FOLLOWING PROLIA ADMINISTRATION. SEVERE HYPOCALCEMIA
RESULTING IN
HOSPITALIZATION, LIFE-THREATENING EVENTS AND FATAL CASES HAVE BEEN
REPORTED. _(5.1)_
THE PRESENCE OF CHRONIC KIDNEY DISEASE-MINERAL BONE DISORDER (CKD-MBD)
MARKEDLY
INCREASES THE RISK OF HYPOCALCEMIA. _(5.1)_
PRIOR TO INITIATING PROLIA IN PATIENTS WITH ADVANCED CHRONIC KIDNEY
DISEASE, EVALUATE
FOR THE PRESENCE OF CKD-MBD. TREATMENT WITH PROLIA IN THESE PATIENTS
SHOULD BE
SUPERVISED BY A HEALTHCARE PROVIDER WITH EXPERTISE IN THE DIAGNOSIS
AND
MANAGEMENT OF CKD-MBD. _(2.2), (5.1)_
RECENT MAJOR CHANGES
Boxed Warning
01/2024
Dosage and Administration (2.2)
01/2024
Warnings and Precautions (5.1)
01/2024
INDICATIONS AND USAGE
Prolia is a RANK ligand (RANKL) inhibitor indicated for treatment:
of postmenopausal women with osteoporosis at high risk for fracture
(1.1)
to increase bone mass in men with osteoporosis at high risk for
fracture (1.2)
of glucocorticoid-induced osteoporosis in men and women at high risk
for fracture (1.3)
to increase bone mass in men at high risk for fracture receiving
androgen deprivation therapy for
nonmetastatic prostate cancer (1.4)
to increase bone mass in women at high risk for fracture receiving
adjuvant aromatase inhibitor therapy
for breast cancer (1.5)
DOSAGE AND ADMINISTRATION
Pregnancy must be ruled out prior to administration of Prolia. (2.1)
Before initiating Prolia in patients with advanced chronic kidney
disease, including dialysis patients,
evaluate for the presence of chronic kidney disease min