Denosumab

Denosumab is an RANK Ligand belonging to pharmacology class of Antiresorptive drugs

Denosumab can be used in the treatment of Increase bone mass in men with osteoporosis, Osteoporosis in postmenopausal women, Giant cell tumor of bone, Hypercalcemia of malignancy, Bone metastases associated with solid tumors

Denosumab Bioavailability is 62%. Time to peak plasma concentration: 10 days and get Metabolized via Ig clearance pathways, resulting in degradation to small peptides and amino acids get excreted Via the reticuloendothelial system with elimination half-life: Approx 25-28 days.

Denosumab is available in the form of Injectable solutions.

The molecule is available in India, Japan, Germany, China.

Denosumab, a monoclonal antibody, binds to receptor activator of nuclear factor kappa-B ligand (RANKL) preventing activation from its receptor, RANK, thus inhibits osteoclast formation, function, and survival thereby reducing bone resorption.

Denosumab is available in injectable solutions.

Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone.

Denosumab is approved for use in the following clinical indications

Increase bone mass in men with osteoporosis, Osteoporosis in postmenopausal women

Adult: 60 mg every 6 mth. Co-administer oral Ca 1,000 mg and vit D ≥400 IU daily.

Giant cell tumor of bone, Hypercalcemia of malignancy

Adult: 120 mg every 4 wk, w/ additional 120 mg doses on days 8 and 15 of the initial 4-wk cycle. Co-administer oral Ca ≥500 mg and vit D ≥400 IU daily.

Bone metastases associated with solid tumours

Adult: 120 mg every 4 wk. Co-administer oral Ca ≥500 mg and vit D ≥400 IU daily.

• Subcutaneous

Increase bone mass in men with osteoporosis, Osteoporosis in postmenopausal women

Adult: 60 mg every 6 mth. Co-administer oral Ca 1,000 mg and vit D ≥400 IU daily.

• Subcutaneous

Giant cell tumour of bone, Hypercalcemia of malignancy

Adult: 120 mg every 4 wk, w/ additional 120 mg doses on days 8 and 15 of the initial 4-wk cycle. Co-administer oral Ca ≥500 mg and vit D ≥400 IU daily.

• Subcutaneous

Bone metastases associated with solid tumours

Adult: 120 mg every 4 wk. Co-administer oral Ca ≥500 mg and vit D ≥400 IU daily.

Injectable solution

60 mg/vial, 70 mg/vial

Injectable solution

Denosumab may be contraindicated in the following conditions:-

• Hypocalcemia

Pre-existing hypocalcemia must be corrected prior to initiating therapy with Denosumab.

• Pregnancy

Denosumab may cause fetal harm when administered to a pregnant woman. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. Denosumab is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

• Hypersensitivity

Denosumab is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. Reactions have included anaphylaxis, facial swelling and urticaria.

• Ocular and auditory disturbances have been reported when Denosumab mesylate was administered over prolonged periods of time, at high doses, or in patients with low ferritin levels. The ocular disturbances observed have been blurring of vision; cataracts after prolonged administration in chronic iron overload; decreased visual acuity including visual loss, visual defects, scotoma; impaired peripheral, color, and night vision; optic neuritis, cataracts, corneal opacities, and retinal pigmentary abnormalities. The auditory abnormalities reported have been tinnitus and hearing loss including high frequency sensorineural hearing loss. In most cases, both ocular and auditory disturbances were reversible upon immediate cessation of treatment.
• Visual acuity tests, slit-lamp examinations, funduscopy and audiometry are recommended periodically in patients treated for prolonged periods of time. Toxicity is more likely to be reversed if symptoms or test abnormalities are detected early.
• Increases in serum creatinine (possibly dose-related), acute renal failure and renal tubular disorders, associated with the administration of Denosumab , have been reported in postmarketing experience. Monitor patients for changes in renal function.
• High doses of Denosumab mesylate and concomitant low ferritin levels have also been associated with growth retardation. After reduction of Denosumab mesylate dose, growth velocity may partially resume to pretreatment rates.
• Adult respiratory distress syndrome, also reported in children, has been described following treatment with excessively high intravenous doses of Denosumab mesylate in patients with acute iron intoxication or thalassemia.

Precautions

General

• Flushing of the skin, urticaria, hypotension, and shock have occurred in a few patients when Denosumab mesylate was administered by rapid intravenous injection. Therefore, Denosumab mesylate should be given intramuscularly or by slow subcutaneous or intravenous infusion.
• Iron overload increases susceptibility of patients to Yersinia enterocolitica and Yersinia pseudotuberculosis infections. In some rare cases, treatment with Denosumab mesylate has enhanced this susceptibility, resulting in generalized infections by providing these bacteria with a siderophore otherwise missing. In such cases, Denosumab mesylate treatment should be discontinued until the infection is resolved.
• In patients receiving Denosumab mesylate, rare cases of mucormycosis, some with a fatal outcome, have been reported. If any of the suspected signs or symptoms occur, Denosumab mesylate should be discontinued, mycological tests carried out and appropriate treatment instituted immediately.
• In patients with severe chronic iron overload, impairment of cardiac function has been reported following concomitant treatment with Denosumab mesylate and high doses of vitamin C (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin C was discontinued. The following precautions should be taken when vitamin C and Denosumab mesylate are to be used concomitantly:
• Vitamin C supplements should not be given to patients with cardiac failure.
• Start supplemental vitamin C only after an initial month of regular treatment with Denosumab mesylate.
• Give vitamin C only if the patient is receiving Denosumab mesylate regularly, ideally soon after setting up the infusion pump.
• Do not exceed a daily vitamin C dose of 200 mg in adults, given in divided doses.

There is no sufficient scientific evidence traceable regarding use and safety of Denosumab in concurrent use with alcohol.

It is not known if Denosumab is present in breast milk.

Denosumab may cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. Denosumab is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

The adverse reactions related to Denosumab can be categorized as

Common Adverse effects:

Back pain, musculoskeletal pain, hypercholesterolemia, hypercalcemia, cystitis, dermatitis, rash, eczema, hypersensitivity (including anaphylaxis)

Less Common Adverse effects:

Dyspnoea, cough, nasopharyngitis, upper resp tract infection.

Rare Adverse effects:

Osteonecrosis of the jaw, atypical femoral fractures.

The clinically relevant drug interactions of Denosumab is briefly summarized here:

May enhance the adverse effect of belimumab.

Increased risk for serious infections and adverse effect w/ immunosuppressants.

The most common side effects of Denosumab includes: Back pain, musculoskeletal pain, hypercholesterolemia, hypercalcemia, cystitis, dermatitis, rash, eczema, hypersensitivity (including anaphylaxis).

Pregnancy Category (FDA): X Risk Summary

Denosumab may cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. Denosumab is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Clinical Considerations

The effects of Denosumab on the fetus are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies, such as denosumab, are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Denosumab therapy, treatment should be discontinued and the patient should consult their physician.

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 at a pharmacologically active dose, 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. 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

Pregnancy Category (AUS):

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Denosumab in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Denosumab during labor and delivery.

Nursing Mothers

It is not known whether Denosumab is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Denosumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Denosumab during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. 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

Pediatric Use

Denosumab is not recommended in pediatric patients. The safety and effectiveness of Denosumab in pediatric patients have not been established. Treatment with Denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Denosumab 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. 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.

Geriatic Use

Of the total number of patients in clinical studies of Denosumab, 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. 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.

Gender

Denosumab may cause fetal harm. The extent to which denosumab is present in seminal fluid is unknown. There is a potential for fetal exposure to denosumab when a man treated with Denosumab has unprotected sexual intercourse with a pregnant partner. The risk of fetal harm is likely to be low. Advise men being treated with Denosumab who have a pregnant partner of this potential risk.

Race

There is no FDA guidance on the use of Denosumab with respect to specific racial populations.

Renal Impairment

No dose adjustment is necessary in patients with renal impairment. In clinical studies, patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis were at greater risk of developing hypocalcemia. Consider the benefit-risk profile when administering Denosumab to patients with severe renal impairment or receiving dialysis. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis.

Hepatic Impairment

No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of Denosumab.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Denosumab in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Denosumab in patients who are immunocompromised.

Pharmacodynamics:

Denosumab, a monoclonal antibody, binds to receptor activator of nuclear factor kappa-B ligand (RANKL) preventing activation from its receptor, RANK, thus inhibits osteoclast formation, function, and survival thereby reducing bone resorption.

Pharmacokinetics:

Absorption Bioavailability: 62%. Time to peak plasma concentration: 10 days.

Metabolism: Metabolised via Ig clearance pathways, resulting in degradation to small peptides and amino acids.

Excretion: Via the reticuloendothelial system. Elimination half-life: Approx 25-28 days.

1. https://www.uptodate.com/contents/ Denosumab -drug-information?search= Denosumab &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Denosumab _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Denosumab ?type=full&mtype=generic#mechanism-of-action