Clodronic Acid

Atypical femur fractures have been reported in patients receiving bisphosphonates for treatment/prevention of osteoporosis. The fractures include subtrochanteric femur (bone just below the hip joint) and diaphyseal femur (long segment of the thigh bone). Some patients experience prodromal pain weeks or months before the fracture occurs. It is unclear if bisphosphonate therapy is the cause for these fractures, although the majority of cases have been reported in patients taking bisphosphonates. Patients receiving long-term (>3 to 5 years) therapy may be at an increased risk. Patients with thigh or groin pain should be assessed for atypical fracture. Discontinue bisphosphonate therapy in patients who develop a femoral shaft fracture.

Infrequently, severe (and occasionally debilitating) bone, joint, and/or muscle pain have been reported during bisphosphonate treatment. The onset of pain ranged from a single day to several months. Consider discontinuing therapy in patients who experience severe symptoms; symptoms usually resolve upon discontinuation. Some patients experienced recurrence when rechallenged with same drug or another bisphosphonate; avoid use in patients with a history of these symptoms in association with bisphosphonate therapy.

May cause irritation to upper gastrointestinal mucosa. Esophagitis, dysphagia, esophageal ulcers, esophageal erosions, and esophageal stricture (rare) have been reported with oral bisphosphonates; risk increases in patients unable to comply with dosing instructions. Strict adherence to dosing instructions is advised. Use with caution in patients unable to remain upright for ≥30 minutes after ingestion and/or with dysphagia, esophageal disease, gastritis, duodenitis, or ulcers (may worsen underlying condition). Discontinue use and evaluate patient if new or worsening symptoms (eg, dyspepsia, dysphagia, retrosternal pain), develop.

Risk of hypocalcemia (often asymptomatic) may be associated with both oral and intravenous use, however chelation of serum calcium observed with intravenous administration can further increase this risk. Interrupting the infusion or reducing the oral dose may be necessary. Correction of severe or symptomatic hypocalcemia may require calcium supplementation.

Hypersensitivity reactions including dyspnea or other respiratory disorders have been observed; use caution in patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis).

Conjunctivitis, uveitis, scleritis, and episcleritis have been observed with bisphosphonates; patients with complicated or severe infection may require therapy discontinuation and should be referred for ophthalmic evaluation.

Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving bisphosphonates. Known risk factors for MRONJ include dental surgery, cancer diagnosis, concomitant therapy (eg, chemotherapy, corticosteroids), poor oral hygiene, and comorbid disorders (anemia, coagulopathy, infection, preexisting oral disease). 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. Other risk factors for MRONJ include dentoalveolar surgery (eg, tooth extraction, dental implants), and preexisting inflammatory dental disease. Risk of MRONJ 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 also increased with intravenous antiresorptive use 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 (AAOMS [Ruggiero 2014]). The manufacturer’s labeling states that during therapy, invasive dental procedures and dental surgery should be avoided if possible; for patients requiring dental procedures, there are no data suggesting whether

Use with caution in renal impairment; may aggravate renal function particularly with IV doses exceeding maximum recommended doses and/or too rapid infusion. Close monitoring of serum creatinine and BUN and adequate hydration are required with renal impairment. Interrupt infusion in patients experiencing deteriorating renal function during therapy. Dose reductions are required for moderate or severe impairment. Use is contraindicated when serum creatinine >5 mg/dL (SI 440 micromole/L). Concurrent drug therapy issues:

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. Other warnings:

[Canadian Boxed Warning]: Clasteon injection should not be administered as a bolus injection; may precipitate acute renal failure as well as severe local reactions and thrombophlebitis. Dilute prior to use; ensure adequate hydration prior to and during infusion. Avoid infiltration/extravasation.