Denosumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Subcutaneous [preservative free]:

Prolia: 60 mg/mL (1 mL) [contains mouse (murine) and/or hamster protein]

Xgeva: 120 mg/1.7 mL (1.7 mL)

Pharmacology

Mechanism of Action

Denosumab is a monoclonal antibody with affinity for nuclear factor-kappa ligand (RANKL). Osteoblasts secrete RANKL; RANKL activates osteoclast precursors and subsequent osteolysis which promotes release of bone-derived growth factors, such as insulin-like growth factor-1 (IGF1) and transforming growth factor-beta (TGF-beta), and increases serum calcium levels. Denosumab binds to RANKL, blocks the interaction between RANKL and RANK (a receptor located on osteoclast surfaces), and prevents osteoclast formation, leading to decreased bone resorption and increased bone mass in osteoporosis. In solid tumors with bony metastases, RANKL inhibition decreases osteoclastic activity leading to decreased skeletal related events and tumor-induced bone destruction. In giant cell tumors of the bone (which express RANK and RANKL), denosumab inhibits tumor growth by preventing RANKL from activating its receptor (RANK) on the osteoclast surface, osteoclast precursors, and osteoclast-like giant cells.

Pharmacokinetics/Pharmacodynamics

Onset of Action

Decreases markers of bone resorption by ~85% within 3 days; maximal reductions observed within 1 month

Hypercalcemia of malignancy: Time to response (median): 9 days; Time to complete response (median): 23 days (Hu 2014)

Time to Peak

Serum: 10 days (range: 3 to 21 days)

Duration of Action

Markers of bone resorption return to baseline within 12 months of discontinuing therapy

Hypercalcemia of malignancy: Duration of response (median): 104 days; Duration of complete response (median): 34 days (Hu 2014)

Half-Life Elimination

~25 to 28 days

Use: Labeled Indications

Bone metastases from solid tumors (Xgeva): Prevention of skeletal-related events in patients with bone metastases from solid tumors.

Giant cell tumor of bone (Xgeva): Treatment of giant cell tumor of bone (in adults and skeletally mature adolescents) that is unresectable or where surgical resection is likely to result in severe morbidity.

Hypercalcemia of malignancy (Xgeva): Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

Multiple myeloma (Xgeva): Prevention of skeletal-related events in patients with multiple myeloma.

Osteoporosis/bone loss (Prolia): Treatment of osteoporosis in postmenopausal females at high risk of fracture; treatment of osteoporosis (to increase bone mass) in males at high risk of fracture; treatment of bone loss (to increase bone mass) in males receiving androgen-deprivation therapy for nonmetastatic prostate cancer; treatment of bone loss (to increase bone mass) in females receiving aromatase inhibitor therapy for breast cancer; treatment of glucocorticoid-induced osteoporosis in patients at high risk of fracture who are initiating or continuing systemic glucocorticoids at a daily dose equivalent to ≥7.5 mg of prednisone for an anticipated duration of at least 6 months (high risk defined as osteoporotic fracture history, multiple risk factors for fracture, or failure of or intolerance to other available osteoporosis therapy).

Use: Off Label

Bone destruction caused by rheumatoid arthritisb

Data from a multicenter, randomized, double-blind, placebo-controlled, phase 2 study supports the use of denosumab (with ongoing methotrexate administration) in the treatment of bone destruction caused by rheumatoid arthritis Cohen 2008.

Contraindications

Prolia: Hypersensitivity (systemic) to denosumab or any component of the formulation; preexisting hypocalcemia; pregnancy

Xgeva: Known clinically significant hypersensitivity to denosumab or any component of the formulation; preexisting hypocalcemia

Dosage and Administration

Dosing: Adult

Note: Correct hypocalcemia prior to initiation of therapy. Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia during therapy.

Bone metastases from solid tumors (prevention of skeletal-related events; Xgeva): SubQ: 120 mg every 4 weeks (Fizazi 2011; Henry 2011; Stopeck 2010).

Giant cell tumor of bone (Xgeva): SubQ: 120 mg once every 4 weeks; during the first month, give an additional 120 mg on days 8 and 15 (Blay 2011; Thomas 2010).

Hypercalcemia of malignancy (Xgeva): SubQ: 120 mg every 4 weeks; during the first month, give an additional 120 mg on days 8 and 15 (Hu 2014).

Multiple myeloma (prevention of skeletal-related events; Xgeva): SubQ: 120 mg every 4 weeks (Raje 2018). Denosumab has a reversible mechanism of action and therefore should not be discontinued abruptly (ASCO [Anderson 2018]).

Osteoporosis/bone loss

(Prolia):

Androgen deprivation therapy-induced bone loss in males with prostate cancer, treatment: SubQ: 60 mg as a single dose, once every 6 months (Smith 2009).

Aromatase inhibitor-induced bone loss in females with breast cancer, treatment: SubQ: 60 mg as a single dose, once every 6 months (Ellis 2008).

Osteoporosis, glucocorticoid-induced (males and females): SubQ: 60 mg as a single dose, once every 6 months (Saag 2018).

Osteoporosis, treatment (males and postmenopausal females): Note: Alternative initial agent if bisphosphonate therapy is not suitable (ES [Eastell 2019]). Prior to use, evaluate and treat any potential causes of secondary osteoporosis (eg, hypogonadism in males) (ES [Watts 2012]).

SubQ: 60 mg as a single dose, once every 6 months.

Discontinuation/interruption of therapy: Bone mineral density (BMD) returns to baseline within 18 to 24 months following discontinuation; bone turnover markers increase within 3 to 6 months and then return to baseline within 24 months following discontinuation. Therefore, a drug holiday is not recommended (Bone 2011; ES [Eastell 2019]). If continued osteoporosis therapy is necessary, discontinuation or interruption of denosumab should not occur without subsequent antiresorptive therapy (eg, bisphosphonate or alternative) to prevent a rebound in bone turnover and to decrease rapid BMD loss and risk of fracture (ES [Eastell 2019]).

Duration of therapy: If fracture risk remains high after initial 5 to 10 years, consider extending therapy or switching to alternative therapy; there are no data on use beyond 10 years (ES [Eastell 2019]).

Missed dose (Prolia): If a dose is missed, administer as soon as possible, then continue dosing every 6 months from the date of the last injection.

Bone destruction caused by rheumatoid arthritis (off-label use; based on limited data): SubQ: 60 mg or 180 mg as a single one time dose and repeated at 6 months (in combination with continued methotrexate); a total of 2 doses was administered in the study (Cohen 2008).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia.

Giant cell tumor of the bone, treatment: Xgeva: Adolescents (skeletally mature) weighing ≥45 kg: SubQ: 120 mg once every 4 weeks; during the first month, give an additional dose of 120 mg on days 8 and 15 (Chawla 2013; Thomas 2010).

Administration

SubQ: Denosumab is intended for SubQ route only and should not be administered IV, IM, or intradermally. Prior to administration, bring to room temperature in original container (allow to stand ~15 to 30 minutes); do not warm by any other method. Solution may contain trace amounts of translucent to white protein particles; do not use if cloudy, discolored (normal solution should be clear and colorless to pale yellow), or contains excessive particles or foreign matter. Avoid vigorous shaking. Administer via SubQ injection in the upper arm, upper thigh, or abdomen; should only be administered by a health care professional.

Dietary Considerations

Ensure adequate calcium and vitamin D intake to prevent or treat hypocalcemia. Calcium 1,000 mg/day and vitamin D ≥400 units/day is recommended in product labeling (Prolia). If dietary intake is inadequate, dietary supplementation is recommended. Females and males should consume:

Calcium: 1,000 mg/day (males: 50 to 70 years) or 1,200 mg/day (females ≥51 years and males ≥71 years) (IOM 2011; NOF 2014).

Vitamin D: 800 to 1,000 units/day (males and females ≥50 years) (NOF 2014). Recommended Dietary Allowance (RDA): 600 units/day (males and females ≤70 years) or 800 units/day (males and females ≥71 years) (IOM 2011).

Storage

Store in original carton at 2°C to 8°C (36°F to 46°F). Do not freeze. Prior to use, bring to room temperature of 25°C (77°F) in original container (usually takes 15 to 30 minutes); do not use any other methods for warming. Use within 14 days once at room temperature. Protect from direct heat and light; do not expose to temperatures >25°C (77°F). Avoid vigorous shaking.

Drug Interactions

Calcimimetic Agents: Denosumab may enhance the hypocalcemic effect of Calcimimetic Agents. Monitor therapy

Immunosuppressants: Denosumab may enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Exceptions: Cytarabine (Liposomal). Monitor therapy

Adverse Reactions

Percentages noted with Prolia (60 mg every 6 months) or Xgeva (120 mg every 4 weeks).

>10%:

Cardiovascular: Peripheral edema (Xgeva: 17% to 24%; Prolia: 5%), hypertension (Prolia: 4%)

Central nervous system: Fatigue (Xgeva: ≤45%), headache (Xgeva: 11% to 24%; Prolia: 4%)

Dermatologic: Skin rash (≤14%), dermatitis (Prolia: ≤11%), eczema (Prolia: ≤11%)

Endocrine & metabolic: Hypophosphatemia (Xgeva: 32%; severe: 10% to 21%), hypocalcemia (Xgeva: 3% to 18%; Prolia: 2%)

Gastrointestinal: Diarrhea (Xgeva: 20% to 34%), nausea (Xgeva: 30% to 32%), decreased appetite (Xgeva: 24%), vomiting (Xgeva: 24%; Prolia 2%), constipation (Xgeva: 21%; Prolia: 3%)

Hematologic & oncologic: Anemia (Xgeva: 21% to 22%), thrombocytopenia (Xgeva: 19%)

Neuromuscular & skeletal: Asthenia (Xgeva: ≤45%), back pain (Xgeva: 21%; Prolia: 5% to 12%), arthralgia (7% to 14%), limb pain (Prolia: 10% to 12%)

Respiratory: Dyspnea (Xgeva: 21% to 27%), cough (Xgeva: 15%), upper respiratory tract infection (Xgeva: 15%; Prolia: 5%)

1% to 10%:

Cardiovascular: Angina pectoris (Prolia: 3%)

Central nervous system: Sciatica (Prolia: 5%)

Endocrine & metabolic: Hypercholesterolemia (Prolia: 7%), hypokalemia (Xgeva: grade 3: 3%); hypomagnesemia (Xgeva: grade 3: 3%), severe hypocalcemia (symptomatic; Xgeva: 2% to 3%; Prolia: <1%)

Gastrointestinal: Upper abdominal pain (Prolia: 3%), flatulence (Prolia: 2%)

Genitourinary: Urinary tract infection (Prolia: 3%)

Hematologic & oncologic: Malignant neoplasm (Prolia: new; 3% to 5%)

Infection: Serious infection (Prolia: 4%)

Neuromuscular & skeletal: Musculoskeletal pain (Prolia: 6%), ostealgia (Prolia: 4%), myalgia (Prolia: 3%), osteonecrosis of the jaw (Xgeva ≤4%; Prolia: <1%), polymyalgia rheumatic (Prolia: 2%)

Ophthalmic: Cataract (Prolia: 5%)

Respiratory: Pneumonia (Xgeva: 8%), nasopharyngitis (Prolia: 7%), bronchitis (Prolia: 4%)

<1%, postmarketing, and/or case reports: Alopecia, anaphylaxis, antibody development, endocarditis, erythema of skin, facial swelling, femur fracture (diaphyseal, subtrochanteric), hypercalcemia (Xgeva, following discontinuation), hypersensitivity reaction, lichenoid eruption, osteomyelitis, pancreatitis, increased parathyroid hormone, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Bone fractures: Atypical femur fractures have been reported in patients receiving denosumab. The fractures may occur anywhere along the femoral shaft (may be bilateral) and commonly occur with minimal to no trauma to the area. Some patients experience prodromal pain weeks or months before the fracture occurs. Because these fractures also occur in osteoporosis patients not treated with denosumab, it is unclear if denosumab therapy is the cause for the fractures; concomitant glucocorticoids may contribute to fracture risk. Advise patients to report new/unusual hip, thigh, or groin pain; and if so, evaluate for atypical/incomplete fracture. Contralateral limb should be assessed if atypical fracture occurs. Consider interrupting therapy in patients who develop an atypical femoral fracture. Following treatment discontinuation, the fracture risk increases, including risk of multiple vertebral fractures; patients with a history of prior fractures or osteoporosis are at higher risk. Vertebral fractures occurred as early as 7 months (average: 19 months) after the last dose of denosumab. Evaluate benefit/risk before initiating denosumab treatment for osteoporosis, especially in patients with prior vertebral fracture. If denosumab is discontinued, evaluate risk for vertebral fracture and consider transitioning to an alternative osteoporosis therapy. Because denosumab is associated with a severe bone turnover rebound following discontinuation, post-denosumab antiresorptive therapy (eg, bisphosphonate therapy or alternative) is suggested to mitigate decline in bone mineral density (ES [Eastell 2019]; Tsourdi 2017). Bisphosphonate therapy following denosumab discontinuation may reduce/prevent bone turnover rebound (Lamy 2017).
• Dermatologic reactions: Dermatitis, eczema, and rash (which are not necessarily specific to the injection site) have been reported. Consider discontinuing if severe symptoms occur.
• Hypersensitivity: Clinically significant hypersensitivity (including anaphylaxis) has been reported. May include throat tightness, facial edema, upper airway edema, lip swelling, dyspnea, pruritus, rash, urticaria, and hypotension. If anaphylaxis or clinically significant hypersensitivity occurs, initiate appropriate management and permanently discontinue.
• Hypercalcemia: Hypercalcemia (clinically significant requiring hospitalization and complicated by acute renal injury) may occur in patients with giant cell tumor of bone and patients with growing skeletons weeks to months following discontinuation of denosumab therapy. Monitor for signs/symptoms of hypercalcemia (eg, nausea, vomiting, headache, decreased alertness), assess serum calcium periodically, and treat accordingly.
• Hypocalcemia: Denosumab may cause or exacerbate hypocalcemia; severe symptomatic cases (including fatalities) have been reported. An increased risk has been observed with increasing renal dysfunction, most commonly severe dysfunction (CrCl <30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels; correct preexisting hypocalcemia prior to therapy. Monitor levels more frequently when denosumab is administered with other drugs that can also lower calcium levels. Use caution in patients with a history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, severe renal impairment/dialysis, treatment with other calcium-lowering agents, or other conditions that would predispose the patient to hypocalcemia; monitor calcium, phosphorus, and magnesium closely during therapy (the manufacturer recommends monitoring within 14 days of injection [Prolia] or during the first weeks of therapy initiation [Xgeva]). Concomitant use of calcimimetic medications may worsen hypocalcemia. Hypocalcemia lasting weeks to months (and requiring frequent monitoring) has been reported in postmarketing analyses. Administer calcium, vitamin D, and magnesium as necessary. Patients with severe renal impairment (CrCl <30 mL/minute) or those on dialysis may also develop marked elevations of serum parathyroid hormone (PTH).
• Infection: Incidence of infections may be increased, including serious skin infections, abdominal, urinary, ear, or periodontal infections. Endocarditis has also been reported following use. Patients should be advised to contact their healthcare provider if signs or symptoms of severe infection or cellulitis develop. Use with caution in patients with impaired immune systems or using concomitant immunosuppressive therapy; may be at increased risk for serious infections. Evaluate the need for continued treatment with serious infection.
• Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving denosumab. ONJ may manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth/periodontal infection, toothache, gingival ulceration/erosion. Risk factors include invasive dental procedures (eg, tooth extraction, dental implants, oral surgery), cancer diagnosis, immunosuppressive therapy, angiogenesis inhibitor therapy, chemotherapy, systemic corticosteroids, poor oral hygiene, use of a dental appliance, ill-fitting dentures, periodontal and/or other preexisting dental disease, diabetes and gingival infections, local infection with delayed healing, anemia, and/or coagulopathy. In studies of patients with cancer, a longer duration of denosumab exposure was associated with a higher incidence of ONJ, although a majority of patients had predisposing factors, including a history of poor oral hygiene, tooth extraction, or the use of a dental appliance. Patients should maintain good oral hygiene during treatment. A dental exam and appropriate preventive dentistry should be performed prior to therapy. The manufacturer's labeling recommends avoiding invasive dental procedures in patients with bone metastases receiving denosumab for prevention of skeletal-related events and to consider temporary discontinuation of therapy in these patients if invasive dental procedure is required. According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), MRONJ has been associated with bisphosphonates and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy; risk is significantly higher in cancer patients receiving antiresorptive therapy compared to patients receiving osteoporosis treatment (regardless of medication used or dosing schedule). MRONJ risk is increased with intravenous antiresorptive therapy compared to the minimal risk associated with oral bisphosphonate use, although risk appears to increase with oral bisphosphonates when duration of therapy exceeds 4 years. The AAOMS suggests that if medically permissible, initiation of denosumab for cancer therapy should be delayed until optimal dental health is attained (if extractions are required, antiresorptive therapy should delayed until the extraction site has mucosalized or until after adequate osseous healing). Once denosumab is initiated for oncologic disease, procedures that involve direct osseous injury and placement of dental implants should be avoided. Patients developing ONJ during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]). According to the manufacturer, discontinuation of denosumab should be considered (based on risk/benefit evaluation) in patients who develop ONJ.
• Musculoskeletal pain: Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported (time to onset of symptoms has varied from one day to several months after initiating therapy). Consider discontinuing use if severe symptoms develop.

Disease-related concerns:

• Breast cancer: The American Society of Clinical Oncology (ASCO)/Cancer Care Ontario (CCO) updated guidelines on the role of bone-modifying agents (BMAs) in metastatic breast cancer patients (ASCO/CCO [Van Poznak 2017]). The guidelines recommend initiating a BMA (denosumab, pamidronate, zoledronic acid) in patients with metastatic breast cancer to the bone. One BMA is not recommended over another (evidence supporting one BMA over another is insufficient). The optimal duration of BMA therapy is not defined; however, the guidelines recommend continuing BMA therapy indefinitely. The analgesic effect of BMAs are modest and BMAs should not be used alone for pain management; supportive care, analgesics, adjunctive therapies, radiation therapy, surgery, and/or systemic anticancer therapy should be utilized.
• Multiple myeloma: The American Society of Clinical Oncology (ASCO) has updated guidelines on the role of BMAs in multiple myeloma (ASCO [Anderson 2018]). The update now includes denosumab as an alternate to zoledronic acid or pamidronate in patients with lytic disease, and as an additional option in adjunctive pain control in patients with pain due to osteolytic disease and patients receiving other interventions for fractures or impending fractures. Denosumab may also be preferred (to zoledronic acid) in patients with renal impairment. The ASCO guidelines recommend continuing the BMA for up to 2 years in multiple myeloma patients; BMAs may then be resumed upon relapse with new onset skeletal-related events. Denosumab has a reversible mechanism of action and therefore should not be discontinued abruptly (refer to Bone fractures [above] for further information).
• Renal impairment: Use with caution in patients with renal impairment (CrCl <30 mL/minute) or patients on dialysis; risk of hypocalcemia is increased. Dose adjustment is not needed when administered at 60 mg every 6 months (Prolia); once-monthly dosing has not been evaluated in patients with renal impairment (Xgeva).

Concomitant drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Latex: Packaging may contain natural latex rubber.

Special populations:

• Pediatric: May impair bone growth in children with open growth plates or inhibit eruption of dentition. Indicated only for the treatment of giant cell tumor of bone in adolescents who are skeletally mature.

Other warnings/precautions:

• Appropriate use: Postmenopausal osteoporosis: For use in females at high risk for fracture which is defined as a history of osteoporotic fracture or multiple risk factors for fracture. May also be used in females who failed or did not tolerate other therapies.
• Duplicate therapy: Do not administer Prolia and Xgeva to the same patient for different indications.
• Long-term therapy: Denosumab therapy results in significant suppression of bone turnover; the long-term effects of treatment are not known, but may contribute to adverse outcomes such as ONJ, atypical fractures, or delayed fracture healing; monitor.

Monitoring Parameters

Serum creatinine, serum calcium, phosphorus and magnesium (especially within the first 14 days of therapy [Prolia] or during the first weeks of therapy initiation [Xgeva]), pregnancy test (prior to treatment initiation in females of reproductive potential); signs/symptoms of hypocalcemia, especially in patients predisposed to hypocalcemia (severe renal impairment, thyroid/parathyroid surgery, malabsorption syndromes, hypoparathyroidism); signs/symptoms of hypercalcemia, including periodic serum calcium (following discontinuation in patients with giant cell tumor of the bone and patients with growing skeletons); infection, or dermatologic reactions; routine oral exam (prior to treatment); dental exam if risk factors for ONJ; signs/symptoms of hypersensitivity.

Osteoporosis: Serial bone mineral density (BMD) should be evaluated at baseline and every 1 to 3 years (usually at ~2 years following initiation of therapy, then more or less frequently depending on patient-specific factors and stability of BMD) (AACE/ACE [Camacho 2016]; ES [Eastell 2019]; NOF [Cosman 2014]); may consider monitoring biochemical markers of bone turnover (eg, fasting serum CTX or urinary NTX) at baseline, 3 months, and 6 months, to assess treatment response (ES [Eastell 2019]).

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to denosumab may cause fetal harm. Denosumab is a humanized monoclonal antibody (IgG₂). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009). Use of Prolia is contraindicated during pregnancy.

Evaluate pregnancy status prior to use in females of reproductive potential. Females of reproductive potential should be advised to use effective contraception during denosumab treatment and for at least 5 months following the last denosumab dose. Studies of denosumab following a single 60 mcg subcutaneous dose in healthy men demonstrated that denosumab is present in the semen in low concentrations (~2% of serum exposure) and therefore unlikely that a female partner or fetus would be exposed during unprotected sex to pharmacologically relevant denosumab concentrations via seminal fluid (Sohn 2016).

Data collection to monitor pregnancy and infant outcomes following exposure to denosumab is ongoing. Health care providers are encouraged to enroll females exposed to denosumab during pregnancy in the Amgen Pregnancy Surveillance Program (1-800-772-6436).

Patient Education

What is this drug used for?

• It is used to treat soft, brittle bones (osteoporosis).
• It is used for bone growth.
• It is used when treating some cancers.
• It is used to treat high calcium levels in patients with cancer.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Constipation
• Abdominal pain
• Lack of appetite
• Nausea
• Vomiting
• Diarrhea
• Back pain
• Common cold symptoms
• Painful extremities

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Low calcium like muscle cramps or spasms, numbness and tingling, or seizures.
• Low phosphate like vision changes, confusion, mood changes, muscle pain, muscle weakness, shortness of breath, difficulty breathing, or difficulty swallowing.
• Infection
• Skin infection
• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting
• Mouth sores
• Swelling of arms or legs
• Jaw pain or edema
• Severe loss of strength and energy
• Severe muscle pain
• Severe joint pain
• Severe bone pain
• Shortness of breath
• Vision changes
• Severe dizziness
• Passing out
• Bruising
• Bleeding
• Severe headache
• High calcium like weakness, confusion, fatigue, headache, nausea and vomiting, constipation, or bone pain.
• Dry skin
• Small bumps or patches on skin
• Leather-like skin
• Bladder pain
• Painful urination
• Change in amount of urine passed
• Passing a lot of urine
• Groin, hip, or thigh pain
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.