Skelid

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Do not crush, chew, or suck the pill. Swallow it whole.

Take each tiludronate tablet with a full glass (6 to 8 ounces) of water. Use only plain water (not mineral water) when taking a tiludronate tablet.

For at least the first 2 hours after taking tiludronate, do not eat or drink anything other than plain water, and do not take any other medicines including vitamins or mineral supplements.

Use tiludronate regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

If you need to have any dental work (especially surgery), tell the dentist ahead of time that you are using tiludronate. You may need to stop using the medicine for a short time.

Your doctor will need to check your progress on a regular basis. Do not miss any scheduled appointments.

Tiludronate is only part of a complete program of treatment that may also include taking calcium and vitamin supplements. Follow your diet, medication, and exercise routines very closely.

Store at room temperature away from moisture and heat.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include vomiting, numbness or tingly feeling around your mouth, fast or slow heart rate, muscle tightness or contraction, overactive reflexes.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance for unwanted effects.

Swallow the tablet whole with a large glass (8 ounces) of plain water. Do not drink mineral water, milk, coffee, juice, or any other liquid when you take the tablet. It is best to take this medicine on an empty stomach, either 2 hours before or 2 hours after eating.

Do not lie down for at least 30 minutes after taking this medicine.

It is important that you eat a well-balanced diet with an adequate amount of calcium and vitamin D while you are taking this medicine. Your doctor can help you choose the best diet for your condition.

If you use calcium supplements, mineral supplements, indomethacin, or aspirin, take them either 2 hours before or 2 hours after you take tiludronate. If you use antacids, wait at least 2 hours after your dose before you take the antacid. If you take these medicines together with tiludronate, it may keep the medicine from working properly.

Tiludronate takes up to 3 months to work. If you feel that the medicine is not working, talk to your doctor. Do not stop taking the medicine without checking with your doctor.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For treating Paget's disease:
    • Adults—400 milligrams (mg) once a day for at least 3 months.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Mechanism of Action

In vitro studies indicate that tiludronate disodium acts primarily on bone through a mechanism that involves inhibition of osteoclastic activity with a probable reduction in the enzymatic and transport processes that lead to resorption of the mineralized matrix.

Bone resorption occurs following recruitment, activation, and polarization of osteoclasts. Tiludronate disodium appears to inhibit osteoclasts through at least two mechanisms:  disruption of the cytoskeletal ring structure, possibly by inhibition of protein-tyrosine-phosphatase, thus leading to detachment of osteoclasts from the bone surface and the inhibition of the osteoclastic proton pump.

Pharmacokinetics

Relative to an intravenous (IV) reference dose, the mean oral bioavailability of tiludronate disodium in healthy male subjects was 6% after an oral dose equivalent to 400 mg tiludronic acid administered after an overnight fast and 4 hours before a standard breakfast. In single-dose studies, bioavailability was reduced by 90% when an oral dose equivalent to 400 mg tiludronic acid was administered with, or 2 hours after, a standard breakfast compared to the same dose administered after an overnight fast and 4 hours before a standard breakfast. However, in clinical studies, efficacy was seen when Skelid was dosed at least 2 hours before or after meals.

After administration of a single dose equivalent to 400 mg tiludronic acid to healthy male subjects, tiludronic acid was rapidly absorbed with peak plasma concentrations of approximately 3 mg/L occurring within 2 hours. In pagetic patients, after repeated administration of doses equivalent to 400 mg/day tiludronic acid (2 hours before or 2 hours after a meal) for durations of 12 days to 12 weeks, average plasma concentrations of tiludronic acid occurring between 1 and 2 hours after dosing ranged between 1 and 4.6 mg/L.

Animal pharmacology studies in rats demonstrate that tiludronic acid is widely distributed to bone and soft tissues. Over a period of days, loss of drug occurs from most tissues with the exception of bone and cartilage. Tiludronate is then slowly released from bone with a half-life in rats of 30 days or longer depending on the status of bone turnover.

After oral administration of doses equivalent to 400 mg/day tiludronic acid to nonpagetic patients with osteoarthrosis, the steady state in bone was not reached after 30 days of dosing. At plasma concentrations between 1 and 10 mg/L, tiludronic acid was approximately 90% bound to human serum protein (mainly albumin).

In laboratory animals, tiludronic acid undergoes little if any metabolism. In vitro, tiludronic acid is not metabolized in human liver microsomes and hepatocytes.

The principal route of elimination of tiludronic acid is in the urine. After IV administration to healthy volunteers, approximately 60% of the dose was excreted in the urine as tiludronic acid within 13 days. Renal clearance is dose independent and is approximately 10 mL/min in healthy subjects. In pagetic patients treated with doses equivalent to 400 mg/day tiludronic acid for 12 days, the mean apparent plasma elimination half-life was approximately 150 hours. The elimination rate from human bone is unknown.

Special Populations

No dosage adjustment in elderly patients is necessary. Plasma concentrations of tiludronic acid were higher in elderly pagetic patients (≥65 years of age); however, this difference was not clinically significant.

Skelid pharmacokinetics have not been investigated in subjects under the age of 18 years.

There were no clinically significant differences in plasma concentrations after repeated administration of tiludronate disodium to male and female pagetic patients.

Pharmacokinetic differences due to race have not been studied.

Skelid is not recommended for patients with severe renal failure (creatinine clearance <30 mL/min) due to lack of clinical experience. After a single oral dose equivalent to 400 mg tiludronic acid, subjects with creatinine clearance between 11 and 18 mL/min had Cmax values (approximately 3 mg/L) in the range of healthy volunteers. However, the plasma elimination half-life was approximately 205 hours, which is longer than that observed in pagetic patients after repeated doses (150 hours) and healthy subjects after single doses (50 hours). These values were obtained in a cross-study comparison between healthy volunteers and pagetic patients.

No dosage adjustment is needed. Since tiludronate undergoes little or no metabolism, no studies were conducted in subjects with hepatic insufficiency.

(See also PRECAUTIONS, Drug Interactions.)  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 and 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 disodium does not displace warfarin from its binding site on protein.

Pharmacodynamics

Paget's disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disorderly bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.

Clinical manifestations of Paget's disease range from no symptoms to severe bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy.

In pagetic patients treated with Skelid 400 mg/day for 3 months, changes in urinary hydroxyproline, a biochemical marker of bone resorption, and in serum alkaline phosphatase, a marker of bone formation, indicate a reduction toward normal in the rate of bone turnover. In addition, reduced numbers of osteoclasts by histomorphometric analysis and radiological improvement of lytic lesions indicate that Skelid can suppress the pagetic disease process.

Clinical Studies

The efficacy of Skelid 400 mg/day treatment was demonstrated in two randomized, double-blind, placebo-controlled multicenter studies and one positive-controlled study. All three studies included male and female patients with Paget's disease of the bone (radiograph examination and level of serum alkaline phosphatase [SAP] at least twice the upper normal limit). In one placebo-controlled study, conducted in North America, patients were randomly assigned to receive a daily dose of placebo or 200 or 400 mg/day Skelid for 3 months followed by an additional 12 weeks without treatment. A second placebo-controlled study of similar design was conducted in the UK.

A positive-controlled study was conducted in Europe with treatment groups of 400 mg/day Skelid for 3 months with a 3-month treatment-free follow-up, 400 mg/day Skelid for 6 months, and 400 mg/day etidronate for 6 months. In all of these studies, the efficacy of Skelid was primarily assessed by SAP activity after 3 and 6 months.

Figure 1

In the placebo-controlled trials, suppression of SAP levels was statistically significantly greater with 400 mg/day Skelid both at the end of treatment (3 months) and on follow-up (6 months) than with placebo (See Figure 1). The proportion of patients demonstrating at least a 50% reduction in SAP at 3 months with 400 mg/day Skelid was 61% in the North American study and 52% in the UK study.

Figure 2

In the positive-controlled trial, six months after the start of dosing, the decrease in SAP levels in patients who ceased dosing after a 3-month course of Skelid was significantly greater than with 6 months of etidronate 400 mg/day, and was equivalent to levels in patients who completed a 6-month course of Skelid (See Figure 2).

Treatment effects of Skelid were similar, regardless of pagetic patients' baseline SAP level, gender or age in the population studied.

Histomorphometry of the bone was studied in 19 pagetic and 29 nonpagetic patients. Bone biopsy results in nonpagetic bone confirmed that Skelid did not impair bone remodeling or induce a significant decline in bone turnover. Results obtained in pagetic and nonpagetic bone indicated no evidence of osteomalacia or accumulation of unmineralized osteoid, and there was no reduction in the mineralization rate.

Skelid is indicated for treatment of Paget's disease of bone (osteitis deformans).

Treatment is indicated in patients with Paget's disease of bone (1) who have a level of serum alkaline phosphatase (SAP) at least twice the upper limit of normal, or (2) who are symptomatic, or (3) who are at risk for future complications of their disease.

Skelid is contraindicated in individuals with known hypersensitivity to any component of this product.

Inability to stand or sit upright for at least 30 minutes.

A single 400-mg daily oral dose of Skelid, taken with 6 to 8 ounces of plain water only, should be administered for a period of 3 months. Beverages other than plain water (including mineral water), food (see below), and some medications (see PRECAUTIONS, Drug Interactions) are likely to reduce the absorption of Skelid (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

Patients should not lie down for at least 30 minutes after taking this medication. In patients who cannot comply with dosing instructions due to mental or physical disability, therapy with Skelid should be used under appropriate supervision (See WARNINGS).

Skelid should not be taken within 2 hours of food.

Calcium or mineral supplements should be taken at least 2 hours before or two hours after Skelid. Aluminum- or magnesium-containing antacids, if needed, should be taken at least two hours after taking Skelid.

Skelid should not be taken within 2 hours of indomethacin.

Following therapy, allow an interval of 3 months to assess response. Specific data regarding retreatment are limited, although results from uncontrolled studies indicate favorable biochemical improvement similar to initial Skelid treatment.

Dose-related scoliosis likely attributable to the pharmacologic properties of this drug was reported in rabbits dosed with this drug during the gestational period. In gestational mice, the administration of this drug showed slight maternal toxicity (decreased body weight gain), increased post-implantation loss, decreased number of fetuses, and decreased fetus body weight. Uncommon malformations of the paw (shortened or missing digits, blood blisters between or in place of digits) were also reported. Maternal toxicity (decreased body weight), reduced percent implantations, increased postimplantation loss, and increased intra-uterine deaths in the rats were observed. There were no teratogenic effects on fetuses. Protracted parturition and maternal death, presumably due to hypocalcemia, occurred when rats were treated from day 15 of gestation to day 25 postpartum. 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. There are no adequate and well-controlled studies in pregnant women. AU TGA pregnancy category B2: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

This drug should not be used during pregnancy unless the benefit outweighs the risk to the fetus. AU TGA pregnancy category: B2 US FDA pregnancy category: C Comment: There is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy.

Summary of Use during Lactation

Because no information is available on the use of tiludronate during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. However, absorption of tiludronate by a breastfed infant is unlikely.

Drug Levels

Tiludronate is highly bound to calcium and is poorly absorbed orally (average in adults 6% on an empty stomach, 0.6% with food), so absorption of tiludronate by a breastfed infant is unlikely.

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Pamidronate

References