Prolia (denosumab)

Correct preexisting hypocalcemia prior to treatment initiation. Supplementation with calcium and vitamin D may be required during treatment. All patients treated with denosumab products for osteoporosis or bone loss indications should receive 1000 mg of calcium daily and >=400 IU of vitamin D daily.

Administer denosumab products by subcutaneous injection using single-dose prefilled syringes and/or single-use vials; refer to the prescribing information of the individual denosumab product for available dosage forms.

Subcutaneous injections of denosumab should be made into the upper arm, upper thigh, or abdomen. Do not administer IV, or by IM or intradermal injection.

Refer to the individual denosumab product labeling for storage information. Do not use after the expiration date stated on the label. Do not shake denosumab products vigorously.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antibody-Based Therapies/Imlifidase

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Imlifidase is a cysteine protease that cleaves immunoglobulin G (IgG), which results in degradation of all subclasses of human and rabbit IgG. Therapies based on human or rabbit IgG may be inactivated if given concurrently with imlifidase.(1)

CLINICAL EFFECTS: Antibody therapies based on human or rabbit IgG may be inactivated and lead to decreased efficacy.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of imlifidase and antibody-based therapies should be closely evaluated for timing of administration to avoid decreased efficacy of the antibody-based therapy.(1) Antibody-based therapies cleaved by imlifidase include, but are not limited to, basiliximab, rituximab, alemtuzumab, adalimumab, denosumab, belatacept, etanercept, rabbit anti-human thymocyte globulin (rATG) and intravenous immunoglobulin (IVIg). The prescribing information recommends the following time intervals for administration of antibody-based therapies after administration of imlifidase: -Equine anti-thymocyte globulin: No time interval needed (may be administered concurrently) -Intravenous immunoglobulin (IVIg): 12 hours -Adalimumab, alemtuzumab, basiliximab, denosumab, etanercept, or rituximab: 4 days -Rabbit anti-human thymocyte globulin (rATG) or belatacept: 1 week In addition, IVIg may contain neutralizing antibodies against imlifidase, which may inactivate imlifidase if IVIg is given before imlifidase. Consider the half-life of IVIg (3-4 weeks) before imlifidase administration to patients treated with IVIg. Eculizumab is not cleaved by imlifidase at the recommended dose level.(1)

DISCUSSION: Imlifidase is a cysteine protease that cleaves IgG, which results in degradation of all subclasses of human and rabbit IgG. Antibody therapies based on human or rabbit IgG may be inactivated if given in connection with imlifidase.(1) IVIg may contain neutralizing antibodies against imlifidase, which may inactivate imlifidase if IVIg is given before imlifidase. In clinical studies, IVIg was not administered within 4 weeks before imlifidase infusion.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Igg Antibodies And Derivatives/Efgartigimod-Alfa

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Efgartigimod-alfa binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medicines that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of efgartigimod-alfa states that efgartigimod-alfa should not be combined with long-term use of FcRn-binding medications. If the medication is essential for the patient, efgartigimod-alfa should be discontinued.(3)

DISCUSSION: Clinical drug interaction studies with efgartigimod-alfa have not been performed. Efgartigimod-alfa may decrease concentrations of compounds that bind to the human FcRn.(3)

Igg Antibodies And Derivatives/Nipocalimab-Aahu

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Nipocalimab-aahu binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medicines that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of nipocalimab-aahu states that nipocalimab-aahu should not be combined with long-term use of FcRn-binding medications. If the medication is essential for the patient, nipocalimab-aahu should be discontinued.(3)

DISCUSSION: Clinical drug interaction studies with nipocalimab-aahu have not been performed. Nipocalimab-aahu may decrease concentrations of compounds that bind to the human FcRn.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Igg Antibodies And Derivatives/Rozanolixizumab-Noli

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Rozanolixizumab-noli binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)

CLINICAL EFFECTS: The effectiveness of medications that bind to FcRn may be decreased.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of rozanolixizumab-noli states that concurrent use with medications that bind to the human neonatal Fc receptor (FcRn) should be closely monitored for reduced effectiveness of these medications. If long-term use of such medications is essential for the patient, consider discontinuing rozanolixizumab-noli and use alternative therapies.(3)

DISCUSSION: Clinical drug interaction studies with rozanolixizumab-noli have not been performed. Rozanolixizumab-noli may decrease concentrations of compounds that bind to the human FcRn.(3)

*Hypocalcemia (correct preexisting hypocalcemia prior to initiating denosumab products).

*History of clinically important hypersensitivity (e.g., systemic hypersensitivity) to denosumab products or any component in the formulation.

*Denosumab products labeled for use in the treatment of osteoporosis or bone loss (Prolia(R)) and its biosimilars are contraindicated in pregnant women.

There are no contraindication contraindications for this drug.

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Congenital long QT syndrome
• Hypocalcemia
• Infection
• Pregnancy

• Diabetes mellitus
• Hypoparathyroidism
• Invasive dental procedure
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Periodontitis
• Thyroid surgery

Adverse effects reported in clinical trials in >5% of patients receiving denosumab for the treatment of osteoporosis and reported more frequently with the drug than with placebo include back pain, extremity pain, musculoskeletal pain, hypercholesterolemia, and cystitis (in postmenopausal women) or back pain, arthralgia, and nasopharyngitis (in men).

Adverse effects reported in clinical trials in >3% of patients receiving denosumab for the treatment of glucocorticoid-induced osteoporosis and reported more frequently with denosumab than with risedronate include back pain, hypertension, bronchitis, and headache.

In clinical trials in patients receiving androgen deprivation or aromatase inhibitor therapy, adverse effects reported in >=10% of patients receiving denosumab for treatment of bone loss and reported more frequently with the drug than with placebo include arthralgia and back pain. Musculoskeletal and extremity pain have also been reported.

Adverse effects reported in clinical trials in >=25% of patients with bone metastases from solid tumors receiving denosumab include fatigue/asthenia, hypophosphatemia, and nausea.

Adverse effects reported in clinical trials in >=10% of patients with multiple myeloma receiving denosumab include diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory infection, rash, and headache.

Adverse effects reported in clinical trials in >=10% of patients receiving denosumab for treatment of giant cell tumor of bone include arthralgia, headache, nausea, back pain, fatigue, and extremity pain.

Adverse effects reported in clinical trials in >20% of patients receiving denosumab for bisphosphonate-refractory hypercalcemia of malignancy include nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

More Frequent

• Dyspnea

Less Frequent

• Hypertension
• Hypokalemia
• Hypomagnesemia

Rare or Very Rare

• Anaphylaxis
• Angina
• Aseptic necrosis of jaw bone
• Atypical femoral fracture
• Cataracts
• Cellulitis
• Cholesteatoma of external ear
• Dental abscess
• DRESS syndrome
• Endocarditis
• Erysipelas
• Hypercalcemia
• Hyperparathyroidism
• Hypersensitivity angiitis
• Hypersensitivity drug reaction
• Hypocalcemia
• Hypotension
• Infection
• Malignancy
• Osteonecrosis of external auditory canal
• Pancreatitis
• Polymyalgia rheumatica
• Severe infection
• Throat constriction
• Vasculitis

More Frequent

• Back pain
• Fatigue
• General weakness
• Hypophosphatemia
• Musculoskeletal pain
• Nausea
• Thrombocytopenic disorder

Less Frequent

• Allergic dermatitis
• Anemia
• Anorexia
• Arthralgia
• Bone pain
• Bronchitis
• Constipation
• Cough
• Cystitis
• Diarrhea
• Dizziness
• Dyspepsia
• Eczema
• Flatulence
• Gastroesophageal reflux disease
• Headache disorder
• Hypercholesterolemia
• Infection of ear
• Insomnia
• Pain in extremities
• Peripheral edema
• Pharyngitis
• Pneumonia
• Pruritus of skin
• Sciatica
• Skin inflammation
• Skin rash
• Spinal osteoarthritis
• Upper abdominal pain
• Upper respiratory infection
• Urinary tract infection
• Vertigo
• Vomiting

Rare or Very Rare

• Alopecia
• Ear itching
• Earache
• Erythema
• Facial edema
• Hearing loss
• Herpes zoster
• Impacted cerumen
• Injection site sequelae
• Lichenoid dermatitis drug eruption
• Tinnitus
• Urticaria

No enhanced messaging available.

Safety and efficacy of denosumab (Xgeva(R)) and its biosimilars have been established for treatment of giant cell tumor of bone in skeletally mature adolescents (12-16 years of age). Safety and efficacy of denosumab have not been established for any other indication in pediatric patients.

Safety and efficacy of denosumab (Prolia(R)) and its biosimilars have not been established in pediatric patients. Cases of hypercalcemia (some requiring hospitalization and/or complicated by acute kidney injury) have been reported in clinical trials of pediatric patients with osteogenesis imperfecta treated with denosumab. Clinical trials of denosumab in osteogenesis imperfecta were terminated early due to these life-threatening events; efficacy for this indication was not demonstrated. A small clinical trial in pediatric patients with glucocorticoid-induced osteoporosis also did not demonstrate efficacy of denosumab for this indication. In pediatric patients <4 years of age, denosumab may adversely affect long-bone growth and dentition based on evidence from animal studies.

Clinically important hypercalcemia has been reported following discontinuance of denosumab therapy in pediatric patients with growing skeletons who received the drug for treatment of giant cell tumor of bone or for other off-label uses. Based on animal data, denosumab potentially may impair bone growth in children with open growth plates and may inhibit eruption of dentition.

Based on findings from animal studies and the mechanism of action of denosumab, the drug may cause fetal harm if administered to pregnant women. Reproduction studies in monkeys have demonstrated fetal loss, stillbirth, postnatal mortality, evidence of absent lymph nodes, abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia, tooth malalignment, and decreased neonatal growth. Some of the observed bone abnormalities recovered once drug exposure ceased following birth. No evidence of maternal harm was observed prior to labor in the studies. A study in mice found that absence of receptor activator of nuclear factor kappa-B ligand (RANKL; the target of denosumab) resulted in fetal lymph node agenesis and postnatal impairment of bone growth and dentition.

Confirm pregnancy status prior to initiation of therapy in females of reproductive potential. Apprise pregnant women and females of reproductive potential of the potential drug-associated risk to the fetus.

It is not known whether denosumab is distributed into human milk; the effects of the drug on breast-fed infants or on milk production are also unknown. Denosumab is distributed into milk in monkeys in concentrations of <=0.5% of those attained in serum at <=1 month after the last dose. Studies in pregnant RANKL knockout mice indicate that denosumab exposure during pregnancy may impair maternal mammary gland development and lactation; however, no such impairment was observed in monkeys.

The manufacturers of Prolia(R)and its biosimilars recommend to not breast-feed during treatment. The manufacturers of Xgeva(R) and its biosimilars state to consider the developmental and health benefits of breast-feeding along with the mother's clinical need for treatment with a denosumab product and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

The manufacturer makes no specific dosage recommendations for geriatric patients.

When the total number of patients studied in clinical trials of denosumab for osteoporosis or bone loss indications is considered, 76% were >=65 years of age, while 27% were >=75 years of age; in clinical trials in men with osteoporosis or in patients with glucocorticoid-induced osteoporosis, 55 or 47%, respectively, of patients were >=65 years of age, while 16 or 17%, respectively, were >=75 years of age.

Of the total number of patients studied in clinical trials of denosumab for cancer-related indications, 44-45% were >=65 years of age, while 16-17% were >=75 years of age.

Although no overall differences in efficacy or safety were observed between geriatric and younger patients and other clinical experience has revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.