Didronel®
`(etidronate disodium)
`
`DESCRIPTION:
`Didronel tablets contain 400 mg of etidronate disodium, the disodium salt of
`(1-hydroxyethylidene) diphosphonic acid, for oral administration. This compound, also
`known as EHDP, regulates bone metabolism. It is a white powder, highly soluble in water,
`with a molecular weight of 250 and the following structural formula:
`
`
`O Na O H O Na
`
`H O
`
`P
`
`C
`
`P
`
`O H
`
`C H3
`
`O
`
`
`
`
`Inactive Ingredients: Each tablet contains magnesium stearate, microcrystalline cellulose,
`and starch.
`
`CLINICAL PHARMACOLOGY:
`
`Didronel acts primarily on bone. It can inhibit the formation, growth, and dissolution of
`hydroxyapatite crystals and their amorphous precursors by chemisorption to calcium
`phosphate surfaces. Inhibition of crystal resorption occurs at lower doses than are required
`to inhibit crystal growth. Both effects increase as the dose increases.
`
`Didronel is not metabolized. The amount of drug absorbed after an oral dose is
`approximately 3%. In normal subjects, plasma half-life (t1/2) of etidronate, based on non-
`compartmental pharmacokinetics is 1 to 6 hours. Within 24 hours, approximately half the
`absorbed dose is excreted in urine; the remainder is distributed to bone compartments from
`which it is slowly eliminated. Animal studies have yielded bone clearance estimates up to
`165 days. In humans, the residence time on bone may vary due to such factors as specific
`metabolic condition and bone type. Unabsorbed drug is excreted intact in the feces.
`Preclinical studies indicate etidronate disodium does not cross the blood-brain barrier.
`
`Didronel therapy does not adversely affect serum levels of parathyroid hormone or calcium.
`
`Paget’s Disease: Paget's disease of bone (osteitis deformans) is an idiopathic, progressive
`disease characterized by abnormal and accelerated bone metabolism in one or more bones.
`Signs and symptoms may include bone pain and/or deformity, neurologic disorders,
`elevated cardiac output and other vascular disorders, and increased serum alkaline
`phosphatase and/or urinary hydroxyproline levels. Bone fractures are common in patients
`with Paget's disease.
`
`Didronel slows accelerated bone turnover (resorption and accretion) in pagetic lesions and,
`to a lesser extent, in normal bone. This has been demonstrated histologically,
`scintigraphically, biochemically, and through calcium kinetic and balance studies. Reduced
`bone turnover is often accompanied by symptomatic improvement, including reduced bone
`pain. Also, the incidence of pagetic fractures may be reduced, and elevated cardiac output
`and other vascular disorders may be improved by Didronel therapy.
`
`
`O
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`Procter & Gamble Pharmaceuticals
`
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`ANTECIP EXHIBIT 2009
`Grunenthal GmbH v. Antecip Bioventures II LLC
`PGR2018-00001
`
`

`

`Didronel (etidronate disodium)
`
`Heterotopic Ossification: Heterotopic ossification, also referred to as myositis ossificans
`(circumscripta, progressiva or traumatica), ectopic calcification, periarticular ossification, or
`paraosteoarthropathy, is characterized by metaplastic osteogenesis. It usually presents with
`signs of localized inflammation or pain, elevated skin temperature, and redness. When
`tissues near joints are involved, functional loss may also be present.
`
`Heterotopic ossification may occur for no known reason as in myositis ossificans
`progressiva or may follow a wide variety of surgical, occupational, and sports trauma (e.g.,
`hip arthroplasty, spinal cord injury, head injury, burns, and severe thigh bruises).
`Heterotopic ossification has also been observed in non-traumatic conditions (e.g., infections
`of the central nervous system, peripheral neuropathy, tetanus, biliary cirrhosis, Peyronie's
`disease, as well as in association with a variety of benign and malignant neoplasms).
`
`Clinical trials have demonstrated the efficacy of Didronel in heterotopic ossification
`following total hip replacement, or due to spinal cord injury.
`
`
`--Heterotopic ossification complicating total hip replacement typically develops
`radiographically 3 to 8 weeks postoperatively in the pericapsular area of the affected hip
`joint. The overall incidence is about 50%; about one-third of these cases are clinically
`significant.
`
`--Heterotopic ossification due to spinal cord injury typically develops radiographically 1 to
`4 months after injury. It occurs below the level of injury, usually at major joints. The
`overall incidence is about 40%; about one-half of these cases are clinically significant.
`
`
`Didronel chemisorbs to calcium hydroxyapatite crystals and their amorphous precursors,
`blocking the aggregation, growth, and mineralization of these crystals. This is thought to be
`the mechanism by which Didronel prevents or retards heterotopic ossification. There is no
`evidence Didronel affects mature heterotopic bone.
`
`INDICATIONS AND USAGE:
`
`Didronel is indicated for the treatment of symptomatic Paget’s disease of bone and in the
`prevention and treatment of heterotopic ossification following total hip replacement or due to
`spinal cord injury. Didronel is not approved for the treatment of osteoporosis.
`
`Paget’s Disease: Didronel is indicated for the treatment of symptomatic Paget's disease of
`
`bone. Didronel therapy usually arrests or significantly impedes the disease process as
`evidenced by:
`
`
`--Symptomatic relief, including decreased pain and/or increased mobility (experienced
`by 3 out of 5 patients).
`
`--Reductions in serum alkaline phosphatase and urinary hydroxyproline levels (30% or
`more in 4 out of 5 patients).
`
`--Histomorphometry showing reduced numbers of osteoclasts and osteoblasts, and
`more lamellar bone formation.
`
`--Bone scans showing reduced radionuclide uptake at pagetic lesions.
`
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`Procter & Gamble Pharmaceuticals
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`Didronel (etidronate disodium)
`
`In addition, reductions in pagetically elevated cardiac output and skin temperature have
`been observed in some patients.
`
`In many patients, the disease process will be suppressed for a period of at least 1 year
`following cessation of therapy. The upper limit of this period has not been determined.
`
`The effects of the Didronel treatment in patients with asymptomatic Paget's disease have
`not been studied. However, Didronel treatment of such patients may be warranted if
`extensive involvement threatens irreversible neurologic damage, major joints, or major
`weight-bearing bones.
`
`Heterotopic Ossification: Didronel is indicated in the prevention and treatment of
`
`heterotopic ossification following total hip replacement or due to spinal cord injury.
`
`Didronel reduces the incidence of clinically important heterotopic bone by about two-thirds.
`Among those patients who form heterotopic bone, Didronel retards the progression of
`immature lesions and reduces the severity by at least half. Follow-up data (at least 9
`months posttherapy) suggest these benefits persist.
`
`In total hip replacement patients, Didronel does not promote loosening of the prosthesis or
`
`impede trochanteric reattachment.
`
`In spinal cord injury patients, Didronel does not inhibit fracture healing or stabilization of the
`
`spine.
`
`CONTRAINDICATIONS:
`
`• Abnormalities of the esophagus which delay esophageal emptying such as stricture
`
`or achalasia.
`• Known hypersensitivity to etidronate disodium or in patients with clinically overt
`
`osteomalacia.
`
`
`
`WARNINGS:
`
`General: Upper Gastrointestinal Adverse Reactions: Didronel, 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 Didronel 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 Didronel 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
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`Procter & Gamble Pharmaceuticals
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`Didronel (etidronate disodium)
`
`recommended full glass (6-8 oz) 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 disability, therapy with Didronel 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.
`
`Paget’s Disease: In Paget's patients the response to therapy may be of slow onset and
`continue for months after Didronel therapy is discontinued. Dosage should not be
`increased prematurely. A 90-day drug-free interval should be provided between courses of
`therapy.
`
`Heterotopic Ossification: No specific warnings.
`
`PRECAUTIONS:
`General: Patients should maintain an adequate nutritional status, particularly an adequate
`intake of calcium and vitamin D.
`
`Therapy has been withheld from some patients with enterocolitis since diarrhea may be
`experienced, particularly at higher doses.
`
`Didronel is not metabolized and is excreted intact via the kidney. Hyperphosphatemia may
`occur at doses of 10 to 20 mg/kg/day, apparently as a result of drug-related increases in
`tubular reabsorption of phosphate. Serum phosphate levels generally return to normal 2 to
`4 weeks posttherapy. There is no experience to specifically guide treatment in patients with
`impaired renal function. Didronel dosage should be reduced when reductions in glomerular
`filtration rates are present. Patients with renal impairment should be closely monitored. In
`approximately 10% of patients in clinical trials of Didronel® I. V. Infusion (etidronate
`
`disodium) for hypercalcemia of malignancy, occasional, mild-to-moderate abnormalities in
`renal function (increases of > 0.5 mg/dl serum creatinine) were observed during or
`immediately after treatment.
`
`Didronel suppresses bone turnover, and may retard mineralization of osteoid laid down
`during the bone accretion process. These effects are dose and time dependent. Osteoid,
`which may accumulate noticeably at doses of 10 to 20 mg/kg/day, mineralizes normally
`posttherapy. In patients with fractures, especially of long bones, it may be advisable to
`delay or interrupt treatment until callus is evident.
`
`Osteonecrosis of the jaw (ONJ): ONJ, which can occur spontaneously, is generally
`
`associated with tooth extraction and/or local infection with delayed healing, and has been
`reported in patients taking bisphosphonates, including Didronel. Known risk factors for
`osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental
`implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy,
`corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other
`pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures).
`
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`Procter & Gamble Pharmaceuticals
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`Didronel (etidronate disodium)
`
`For patients requiring invasive dental procedures, discontinuation of bisphosphonate
`treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or
`oral surgeon should guide the management plan of each patient based on individual
`benefit/risk assessment.
`
`Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should
`receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ
`may exacerbate the condition. Discontinuation of bisphosphonate therapy should be
`considered based on individual benefit/risk assessment.
`
`Musculoskeletal Pain: In postmarketing experience, there have been infrequent reports of
`severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking
`bisphosphonates (see ADVERSE REACTIONS). 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 medication. A subset had recurrence of symptoms when
`rechallenged with the same drug or another bisphosphonate.
`
`Paget’s Disease: In Paget's patients, treatment regimens exceeding the recommended
`(see DOSAGE AND ADMINISTRATION) daily maximum dose of 20 mg/kg or continuous
`administration of medication for periods greater than 6 months may be associated with
`osteomalacia and an increased risk of fracture.
`
`Long bones predominantly affected by lytic lesions, particularly in those patients
`unresponsive to Didronel therapy, may be especially prone to fracture.
`
`Patients with predominantly lytic lesions should be monitored radiographically and
`biochemically to permit termination of Didronel in those patients unresponsive to treatment.
`
`Drug Interactions: There have been isolated reports of patients experiencing increases in
`their prothrombin times when etidronate was added to warfarin therapy. The majority of
`these reports concerned variable elevations in prothrombin times without clinically significant
`sequelae. Although the relevance of these reports and any mechanism of coagulation
`alterations is unclear, patients on warfarin should have their prothrombin time monitored.
`
`Carcinogenesis: Long-term studies in rats have indicated that Didronel is not
`carcinogenic.
`
`Pregnancy: 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
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`Didronel (etidronate disodium)
`
`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. Didronel
`
`(etidronate disodium) should be used during pregnancy only if the potential benefit justifies
`the potential risk to the fetus.
`
`Nursing Mothers: 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 Didronel is
`administered to a nursing woman.
`
`Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
`Pediatric patients have been treated with Didronel, at doses recommended for adults, to
`prevent heterotopic ossifications or soft tissue calcifications. A rachitic syndrome has been
`reported infrequently at doses of 10 mg/kg/day and more for prolonged periods approaching
`or exceeding a year. The epiphyseal radiologic changes associated with retarded
`mineralization of new osteoid and cartilage, and occasional symptoms reported, have been
`reversible when medication is discontinued.
`
`Geriatric Use: Clinical studies of Didronel did not include sufficient numbers of subjects
`aged 65 and over to determine whether they respond differently from younger subjects.
`Other reported clinical experience has not identified differences in responses between
`elderly and younger patients. In general, dose selection for an elderly patient should be
`cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function,
`and of concomitant disease or other drug therapy. This drug is known to be substantially
`excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients
`with impaired renal function. Because elderly patients are more likely to have decreased
`renal function, care should be taken when prescribing this drug therapy. As stated in
`PRECAUTIONS, Didronel dosage should be reduced when reductions in glomerular
`filtration rates are present. In addition, patients with renal impairment should be closely
`monitored.
`
`ADVERSE REACTIONS:
`
`The incidence of gastrointestinal complaints (diarrhea, nausea) is the same for Didronel 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,
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`Didronel (etidronate disodium)
`
`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, Stevens-
`Johnson 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.
`
`OVERDOSAGE:
`
`Clinical experience with acute Didronel overdosage is extremely limited. Decreases in
`serum calcium following substantial overdosage may be expected in some patients. Signs
`and symptoms of hypocalcemia also may occur in some of these patients. Some patients
`may develop vomiting. In one event, an 18-year-old female who ingested an estimated
`single dose of 4000 to 6000 mg (67 to 100 mg/kg) of Didronel was reported to be mildly
`hypocalcemic (7.52 mg/dl) and experienced paresthesia of the fingers. Hypocalcemia
`resolved 6 hours after lavage and treatment with intravenous calcium gluconate. A 92-year­
`old female who accidentally received 1600 mg of etidronate disodium per day for 3.5 days
`experienced marked diarrhea and required treatment for electrolyte imbalance. Orally
`administered etidronate disodium may cause hematologic abnormalities in some patients
`(see ADVERSE REACTIONS).
`
`Etidronate disodium suppresses bone turnover and may retard mineralization of osteoid laid
`down during the bone accretion process. These effects are dose and time dependent.
`Osteoid which may accumulate noticeably at doses of 10 to 20 mg/kg/day of chronic,
`continuous dosing mineralizes normally posttherapy.
`
`Prolonged continuous treatment (chronic overdosage) has been reported to cause nephrotic
`syndrome and fracture.
`
`Gastric lavage may remove unabsorbed drug. Standard procedures for treating
`hypocalcemia, including the administration of Ca++ intravenously, would be expected to
`restore physiologic amounts of ionized calcium and relieve signs and symptoms of
`hypocalcemia. Such treatment has been effective.
`
`DOSAGE AND ADMINISTRATION:
`
`Didronel should be taken as a single, oral dose. As with other bisphosphonates, it is
`recommended that Didronel should be swallowed with a full glass of water (6 to 8 oz).
`Patients should not lie down after taking the medication. However, should gastrointestinal
`discomfort occur, the dose may be divided. To maximize absorption, patients should avoid
`taking the following items within two hours of dosing:
`
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`Didronel (etidronate disodium)
`
`--Food, especially food high in calcium, such as milk or milk products.
`
`--Vitamins with mineral supplements or antacids which are high in metals such as
`calcium, iron, magnesium, or aluminum.
`
`
`Paget’s Disease: Initial Treatment Regimens: 5 to 10 mg/kg/day, not to exceed 6
`
`months, or 11 to 20 mg/kg/day, not to exceed 3 months.
`
`The recommended initial dose is 5 mg/kg/day for a period not to exceed 6 months. Doses
`above 10 mg/kg/day should be reserved for when 1) lower doses are ineffective or 2) there
`is an overriding need to suppress rapid bone turnover (especially when irreversible
`neurologic damage is possible) or reduce elevated cardiac output. Doses in excess of 20
`mg/kg/day are not recommended.
`
`Retreatment Guidelines: Retreatment should be initiated only after 1) a Didronel-free
`period of at least 90 days and 2) there is biochemical, symptomatic or other evidence of
`active disease process. It is advisable to monitor patients every 3 to 6 months although
`some patients may go drug free for extended periods. Retreatment regimens are the same
`as for initial treatment. For most patients the original dose will be adequate for retreatment.
`If not, consideration should be given to increasing the dose within the recommended
`guidelines.
`
`Heterotopic Ossification: The following treatment regimens have been shown to be
`effective:
`
`--Total Hip Replacement Patients: 20 mg/kg/day for 1 month before and 3 months after
`surgery (4 months total).
`
`--Spinal Cord Injured Patients: 20 mg/kg/day for 2 weeks followed by 10 mg/kg/day for 10
`weeks (12 weeks total). Didronel therapy should begin as soon as medically feasible
`following the injury, preferably prior to evidence of heterotopic ossification.
`
`Retreatment has not been studied.
`
`HOW SUPPLIED:
`
`Didronel is available as 400-mg, white, scored, capsule-shaped tablets with "N E" on one
`face and "406" on the other.
`
`
`
`Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
`
`[see USP Controlled Room Temperature]
`
`Mfg. by:
`
`Norwich Pharmaceuticals, Inc.
`
`North Norwich, NY 13814
`
`Dist. by:
`
`Procter & Gamble Pharmaceuticals, Inc.
`TM Owner, Cincinnati, OH 45202
`REVISED: DECEMBER 2009
`
`
`NDC 0149-0406-60 bottle of 60
`
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`Procter & Gamble Pharmaceuticals
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