Etidronate Other names: Disodium etidronate 1-hydroxyethane Etidronic acid 1,1-diphosphonic acid

Teratogenic Effects: Pregnancy Category C. In teratology and developmental toxicity studies conducted in rats and rabbits treated with dosages of up to 100 mg/kg (5 to 20 times the clinical dose), no adverse or teratogenic effects have been observed in the offspring. Etidronate disodium has been shown to cause skeletal abnormalities in rats when given at oral dose levels of 300 mg/kg (15 to 60 times the human dose). Other effects on the offspring (including decreased live births) are at dosages that cause significant toxicity in the parent generation and are 25 to 200 times the human dose. The skeletal effects are thought to be the result of the pharmacological effects of the drug on bone.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied.

There are no adequate and well-controlled studies in pregnant women. Etidronate (etidronate disodium) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when etidronate is administered to a nursing woman.

Long-term studies in rats have indicated that Didronel is not carcinogenic.

The incidence of gastrointestinal complaints (diarrhea, nausea) is the same for etidronate at 5 mg/kg/day as for placebo, about 1 patient in 15. At 10 to 20 mg/kg/day the incidence may increase to 2 or 3 in 10. These complaints are often alleviated by dividing the total daily dose.

Paget’s Disease: In Paget’s patients, increased or recurrent bone pain at pagetic sites, and/or the onset of pain at previously asymptomatic sites has been reported. At 5 mg/kg/day about 1 patient in 10 (versus 1 in 15 in the placebo group) report these phenomena. At higher doses the incidence rises to about 2 in 10. When therapy continues, pain resolves in some patients but persists in others.

Heterotopic Ossification: No specific adverse reactions.

Worldwide Postmarketing Experience

The worldwide postmarketing experience for etidronate disodium reflects its use in the following approved indications: Paget’s disease, heterotopic ossification, and hypercalcemia of malignancy. It also reflects the use of etidronate disodium for osteoporosis where approved in countries outside the US. Other adverse events that have been reported and were thought to be possibly related to etidronate disodium include the following: alopecia; arthropathies, including arthralgia and arthritis; bone fracture; esophagitis; glossitis; hypersensitivity reactions, including angioedema, follicular eruption, macular rash, maculopapular rash, pruritus, StevensJohnson syndrome, and urticaria; osteomalacia; neuropsychiatric events, including amnesia, confusion, depression, and hallucination; and paresthesias.

In patients receiving etidronate disodium, there have been rare reports of agranulocytosis, pancytopenia, and a report of leukopenia with recurrence on rechallenge. In addition, there have been rare reports of exacerbation of asthma. Exacerbation of existing peptic ulcer disease including perforation has been reported rarely.

In osteoporosis clinical trials, headache, gastritis, leg cramps, and arthralgia occurred at a significantly greater incidence in patients who received etidronate as compared with those who received placebo.