SKELID Tablet Ref.[50227] Active ingredients: Tiludronic acid

SKELID, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when SKELID is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or ulcers).

Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue SKELID and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6-8oz) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see DOSAGE AND ADMINISTRATION). In patients who cannot comply with dosing instructions due to mental or physical disability, therapy with SKELID should be used under appropriate supervision.

There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials.

The safety of SKELID 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 SKELID 400 mg/day are presented in the table below.

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

Adverse events associated with SKELID usually have been mild, and generally have not required discontinuation of therapy. In two placebo-controlled trials, 1.3% of patients receiving 400 mg SKELID 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 SKELID 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 SKELID has not been established.

SKELID is not recommended for patients with severe renal failure, for example, those with creatinine clearance <30 mL/min (see CLINICAL PHARMACOLOGY, Renal Insufficiency).

Osteonecrosis, primarily in the jaw, has been reported in patients treated with bisphosphonates. Most cases have been in cancer patients undergoing dental procedures, but some have occurred in patients with postmenopausal osteoporosis or other diagnoses. Known risk factors for osteonecrosis include a diagnosis of cancer, concomitant therapies (e.g., chemotherapy, radiotherapy, corticosteroids), and co-morbid disorders (e.g., anemia, coagulopathy, infection, pre-existing dental disease). Most reported cases have been in patients treated with bisphosphonates intravenously but some have been in patients treated orally.

For patients who develop osteonecrosis of the jaw (ONJ) while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Musculoskeletal Pain

In post marketing experience, severe and occasionally incapaciting bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. However, such reports have been infrequent. This category of drugs includes SKELID. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Patients receiving SKELID should be instructed to:

1. Take SKELID with 6 to 8 ounces of plain water.
2. Not lie down for at least 30 minutes after taking this medication.
3. SKELID should not be taken within 2 hours of food.
4. Maintain adequate vitamin D and calcium intake.
5. Calcium supplements, aspirin, and indomethacin should not be taken within 2 hours before or 2 hours after SKELID.
6. Aluminum- or magnesium-containing antacids, if needed, should be taken at least 2 hours after taking SKELID.

The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein.

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. SKELID 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 SKELID is administered to a nursing woman.

Safety and effectiveness of SKELID in pediatric patients have not been established.