Tiludronic acid

Pregnancy Category C

In a teratology study in rabbits dosed during days 6-18 of gestation at 42 mg/kg/day and 130 mg/kg/day (2 and 5 times the 400 mg/day human dose based on body surface area), there was dose-related scoliosis likely attributable to the pharmacologic properties of the drug.

Mice receiving 375 mg/kg/day tiludronic acid (7 times the 400 mg/day human dose based on body surface area, mg/m²) for days 6-15 of gestation showed slight maternal toxicity (decreased body weight gain), increased post-implantation loss, decreased number of fetuses/dam, and decreased fetus body weight. Uncommon malformations of the paw (shortened or missing digits, blood blisters between or in place of digits) were present in six fetuses at 375 mg/kg/day, all from the same litter.

Maternal toxicity (decreased body weight) was also observed in a teratology study in rats dosed during days 6-18 of gestation at 375 mg/kg/day tiludronic acid (10 times the 400 mg/day human dose based on body surface area, mg/m²). There were reduced percent implantations, increased postimplantation loss, and increased intra-uterine deaths in the rats. There were no teratogenic effects on fetuses.

Protracted parturition and maternal death, presumably due to hypocalcemia, occurred at 75 mg/kg/day tiludronic acid (two times the 400 mg/day human dose based on body surface area, mg/m²) when rats were treated from day 15 of gestation to day 25 postpartum.

There are no adequate and well-controlled studies in pregnant women. Tiludronic acid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) 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 established.

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

Carcinogenicity studies have not yet been completed.

Tiludronate was not genotoxic in the following assays: an in vitro microbial mutagenesis assay with and without metabolic activation, a human lymphocyte assay, a yeast cell assay for forward mutation and mitotic crossing over, or the in vivo mouse micronucleus test.

Tiludronate had no effect on rat fertility (male or female) at exposures up to two times the 400 mg/day human dose, based on surface area, mg/m² (75 mg/kg/day tiludronic acid dose).

The safety of tiludronic acid has been studied in more than 1100 patients, and the adverse experience profile is similar between controlled and uncontrolled clinical trials. Adverse events occurring in placebo-controlled trials of pagetic patients treated with tiludronic acid 400 mg/day are presented in the table below.

The most frequently occurring adverse events in patients who received tiludronic acid 400 mg/day were in the gastrointestinal body system: nausea (9.3%), diarrhea (9.3%), and dyspepsia (5.3%).

Adverse events associated with tiludronic acid usually have been mild, and generally have not required discontinuation of therapy. In two placebo-controlled trials, 1.3% of patients receiving 400 mg tiludronic acid and 5.4% of patients receiving placebo discontinued therapy due to any clinical adverse event.

Adverse Events^a (%) Reported^b in >2% of Pagetic Patients from Placebo-Controlled Studies:

Other adverse events not listed in the table above but reported in ≥1% of pagetic patients treated with tiludronic acid in all clinical trials of at least one month duration, regardless of dose and causality assessment, are listed below. The adverse event terms within each body system are listed in the order of decreasing frequency occurring in the population.

Body as a Whole: Asthenia, syncope, fatigue

Cardiovascular: Hypertension

Central and Peripheral Nervous Systems: Vertigo, involuntary muscle contractions

Gastrointestinal: Abdominal pain, constipation, dry mouth, gastritis

Musculoskeletal: Fracture pathological

Psychiatric: Anorexia, somnolence, anxiety, nervousness, insomnia

Respiratory System: Bronchitis

Skin and Appendages: Pruritus, increased sweating

Urinary System: Urinary tract infection

Vascular (extracardiac): Flushing

Stevens-Johnson type syndrome has been observed rarely; the causality relationship of this to tiludronic acid has not been established.