SKELID®
`
`(tiludronate disodium)
`
`
`DESCRIPTION
`
`SKELID is a bisphosphonate characterized by a (4-chlorophenylthio) group on the
`carbon atom of the basic P-C-P structure common to all bisphosphonates. Its generic name is
`tiludronate disodium. Tiludronate disodium is the hydrated hemihydrate form of the disodium
`
`salt of tiludronic acid. Its chemical name is [[(4-Chlorophenyl) thio]methylene]bis[phosphonic
`acid], disodium salt, and its structural formula is as follows:
`
`
`
`
`
`
`
`tiludronate disodium
`(molecular weight 380.6)
`
`
`
`SKELID tablets for oral administration contain 240 mg tiludronate disodium, which is
`the molar equivalent of 200 mg tiludronic acid. SKELID tablets also contain sodium lauryl
`
`sulfate, hydroxypropyl methylcellulose 2910, crospovidone, magnesium stearate, and lactose
`monohydrate.
`
`CLINICAL PHARMACOLOGY
`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
`Absorption
`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
`
`ANTECIP EXHIBIT 2010
`Grunenthal GMBH v. Antecip Bioventures II LLC
`PGR2018-00001
`
`Page 1
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`

`

` 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.
`
`Distribution
`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).
`
`Metabolism
`In laboratory animals, tiludronic acid undergoes little if any metabolism. In vitro,
`
`tiludronic acid is not metabolized in human liver microsomes and hepatocytes.
`
`Elimination
`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
`Geriatric: 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.
`Pediatric: SKELID pharmacokinetics have not been investigated in subjects under the
`age of 18 years.
`Gender: There were no clinically significant differences in plasma concentrations after
`repeated administration of tiludronate disodium to male and female pagetic patients.
`Race: Pharmacokinetic differences due to race have not been studied.
`Renal Insufficiency: 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,
`
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`

`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.
`Hepatic Insufficiency: No dosage adjustment is needed. Since tiludronate undergoes
`little or no metabolism, no studies were conducted in subjects with hepatic insufficiency.
`Drug-Drug Interactions: (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.
`
`
`Mean
`
`(SD)
`
`
`
`
`
`
`
`
`2.66 (1.22) mg/L
`0.54 (0.14) L/hr
`
`Summary of Pharmacokinetic Parameters
`
`in the Normal Population
`
`
`
`
`
`
`
`Parameter
`
`Absolute bioavailability of two 200-mg tablets taken
`
`4 hrs before standard breakfast
`
`
`
`
`Time to peak plasma concentration (taken 4 hrs before first meal
`of day, n=151)
`
`
`
`
`
`
`
`Maximum plasma concentration after a single 400-mg dose
`(taken 4 hrs before first meal of day, n=151)
`
`
`
`Renal clearance after IV administration of 20-mg dose
`
`
`*Bioavailability was reduced by 90% when this single oral dose of 400 mg was administered
`
`with, or 2 hours after, a standard breakfast.
`
`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.
`
`
`6% (2%)*
`
`1.5 (0.9) hr
`
`
`
`
`
`
`
`
`
`
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`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.
`
`
`
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`
`
`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.
`
`
`
`INDICATIONS AND USAGE
`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.
`
`CONTRAINDICATIONS
`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.
`
`WARNINGS
`
`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
`
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`

`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.
`
`
`PRECAUTIONS
`General
`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.
`
`
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`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.
`
`Information for Patients
`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.
`
`
`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 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.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`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).
`
`Pregnancy
`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
`
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`

`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.
`
`Nursing Mothers
`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.
`
`Pediatric Use
`Safety and effectiveness of SKELID in pediatric patients have not been established.
`
`
`ADVERSE REACTIONS
`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.
`
`
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`
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`
`
`BODY AS A WHOLE
`Pain
`Back Pain
`Accidental Injury
`Influenza-like Symptoms
`
`Chest Pain
`Peripheral Edema
`
`CARDIOVASCULAR, GENERAL
`Dependent Edema
`
`
`Central and Peripheral Nervous Systems
`Headache
`Dizziness
`Paresthesia
`
`ENDOCRINE
`Hyperparathyroidism
`
`GASTROINTESTINAL
`Diarrhea
`Nausea
`Dyspepsia
`Vomiting
`Flatulence
`Tooth Disorder
`
`Metabolic and Nutritional
`Vitamin D Deficiency
`
`Musculoskeletal System
`Arthralgia
`Arthrosis
`
`Resistance Mechanism
`Infection
`
`Respiratory System
`Rhinitis
`Sinusitis
`Upper Respiratory Tract Infection
`Coughing
`Pharyngitis
`
`
` Adverse Eventsa (%) Reportedb in > 2% of Pagetic Patients
` from Placebo-Controlled Studies
`
`SKELID
`
`400 mg/day
`(n=75)
`
`21.3
`8.0
`4.0
`4.0
`2.7
`2.7
`
`
`2.7
`
`
`6.7
`4.0
`4.0
`
`
`2.7
`
`
`9.3
`9.3
`5.3
`4.0
`2.7
`2.7
`
`
`2.7
`
`
`2.7
`2.7
`
`
`2.7
`
`
`5.3
`5.3
`5.3
`2.7
`2.7
`
`
`Placebo
`(n=74)
`
`23.0
`8.1
`2.7
`5.4
`0
`1.4
`
`
`0
`
`
`12.2
`6.8
`0
`
`
`0
`
`
`4.1
`5.4
`8.1
`0
`0
`1.4
`
`
`2.7
`
`
`5.4
`0
`
`
`0
`
`
`0
`1.4
`14.9
`2.7
`1.4
`
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`
`Skin and Appendage
`Rash
`Skin Disorder
`
`Vision
`Cataract
`Conjunctivitis
`Glaucoma
`
`
`a Reported using WHO terminology
`
`b All events reported, irrespective of causality
`
`
`
`
`2.7
`2.7
`
`
`2.7
`2.7
`2.7
`
`
`
`1.4
`1.4
`
`
`0
`0
`0
`
`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.
`
`OVERDOSAGE
`Based on the known action of tiludronate, hypocalcemia is a potential consequence of
`SKELID overdose. In one patient with hypercalcemia of malignancy, intravenous administration
`of high doses of SKELID (800 mg/day total dose, 6 mg/kg/day for 2 days) was associated with
`acute renal failure and death.
`No specific information is available on the treatment of overdose with SKELID. Dialysis
`would not be beneficial. Standard medical practices may be used to manage renal insufficiency
`or hypocalcemia, if signs of these develop.
`
`DOSAGE AND ADMINISTRATION
`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).
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`

`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.
`
`HOW SUPPLIED
`SKELID is supplied as white to practically white, biconvex round tablets containing 240
`mg tiludronate disodium, which is the molar equivalent of 200 mg tiludronic acid. SKELID
`tablets are engraved with “S.W” on one side and “200” on the other side and packaged in foil
`strips in cartons of 56 tablets per carton (0024-1800-16).
`
`Storage
`SKELID should be stored at 25° C (77° F); excursions permitted to 15° C to 30° C (59° F
`to 86° F) [see USP Controlled Room Temperature]. Tablets should not be removed from the foil
`strips until they are to be used.
`
`sanofi-aventis U.S. LLC
`Bridgewater, NJ 08807
`
`Country of origin: France
`
`Revised March 2010
`
`
`
`©2009 sanofi-aventis U.S. LLC
`
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`