Procter & Gamble Pharmaceuticals
Bone Metabolism Regulator
Action And Clinical Pharmacology: The Didrocal therapy is a nonhormonal treatment consisting of etidronate disodium administered for 14 days followed by calcium carbonate administered for the next 76 days.
Etidronate Disodium: Etidronate disodium is a bisphosphonate (diphosphonate) that inhibits bone resorption, primarily through the drug’s effect on osteoclasts. Etidronate disodium owes its highly selective bone effects to its ability to adsorb to hydroxyapatite on the bone surface.
Two mechanisms of action contribute to increases in bone mass and maintenance of trabecular integrity: 1) etidronate significantly decreases activation frequency of new bone-remodeling cycles, and 2) etidronate significantly decreases resorption cavity depth without reducing the ability of osteoblasts to fill resorption cavities with normal bone.
The therapy has been shown to decrease activation frequency by about 50%. In clinical trials, the reduction in bone turnover was accompanied by a significant decrease in serum alkaline phosphatase after 2 to 4 cycles of treatment. Trends toward a reduced urinary hydroxyproline/creatinine ratio were also observed. These changes remained within normal laboratory limits and were not progressive.
Etidronate disodium is not metabolized. The amount of drug absorbed after an oral dose is approximately 3.5%. Within 24 hours, approximately half the absorbed dose is excreted in the urine; the remainder is distributed to bone compartments from which it is slowly eliminated. In humans, the residence time on bone may vary due to such factors as specific metabolic condition and bone type. The plasma half-life (t1/2) of etidronate disodium is between 1 and 6 hours; however, the half-life of the drug on bone is in excess of 90 days. Unabsorbed drug is excreted intact in the feces.
Etidronate does not adversely affect serum levels of parathyroid hormone or calcium. In osteoporotic patients, occasional transient hyperphosphatemia has been observed, apparently due to an etidronate-induced increase in renal tubular reabsorption of phosphate. No adverse effects or clinical findings have been associated with the hyperphosphatemia.
Calcium Carbonate: Absorption of calcium carbonate occurs primarily in the more proximal segments of the small bowel. Approximately 30% of an ingested dose is absorbed, although absorption can be augmented by factors such as intake of vitamin D or a vitamin D metabolite. Calcium excretion in urine is the net result of the quantity filtered and the amount reabsorbed. Unabsorbed calcium is excreted in the feces.
The Didrocal regimen design was intended to suppress the resorptive activity of osteoclasts, while allowing normal bone formation to take place during the rest of the remodeling cycle. Thus a 14-day period of daily etidronate is followed by 76 days of calcium supplementation.
Figure 1 (see company’s original product monograph) shows reconstruction of the remodeling cycle in patients after 60 weeks of calcium alone or cyclical etidronate therapy. Several aspects are evident in the etidronate-treated group related to decrease in the rate of bone turnover and depth of resorption during bone remodeling.
First, the entire remodeling cycle is prolonged, resulting in a slower rate of resorption and formation, which then results in a fewer number of overall skeletal remodeling sites. This produces an increase in overall skeletal bone mass as remodeling spaces are filled in and largely accounts for the clinically relevant increases in bone mass and protection against fracture that have been observed.
Second, there is a decrease in the number of resorptive events ongoing at any one time in the skeleton. With a reduction in the number of resorption cavities, a decreased risk of trabecular perforation or generation of “stress risers” is accomplished, aiding overall bone strength over and above the increases in bone mass, per se.
Finally, there is a reduction in the depth of resorption (resorption depth, rD) in the etidronate-treated patients with maintenance of a normal amount of new bone formation (mean wall thickness, MWT). Consequently, the balance of resorption and formation is moved from negative (-1 micron) to positive (+1.5 micron) so that bone is no longer lost with each remodeling event. This outcome effectively reverses the negative bone balance that occurs with menopause, which is otherwise, part of the pathogenesis of postmenopausal osteoporosis.
Overall, these findings largely explain the clinical outcomes of etidronate cyclical therapy through a salutary modulation of the bone turnover process.
However, it should be noted that in analyses of these and other data, it became apparent that the duration of resorptive and formative processes in these patient populations are in general longer than the etidronate and calcium phases of the Didrocal cyclical therapy. Again referring to Figure 1, the resorptive period was 32 days in duration in the calcium control group, with formation taking 186 days, both periods being longer than the 14 and 76 days used for administration of etidronate and calcium, respectively. It is therefore evident that the intermittent use of this modulator of bone metabolism does not require exact matching of individual remodeling cycles to produce the observed increases in bone mass and maintenance of bone quality.
Indications And Clinical Uses: For the treatment of established postmenopausal osteoporosis diagnosed by means of objective measuring techniques such as bone densitometry (a bone mineral density of more than 2.67 standard deviations below the young adult mean) or by radiographic evaluation of the spine (Â³2 vertebral fractures) in women at least 8 years postmenopause. The assessment of vertebral fractures is based upon a minimum 25% reduction in the height of vertebral bodies (anterior, posterior, or central) on lateral radiographs of the spine.
In a minority of patients bone mineral density measurements of the lumbar spine are falsely elevated by the presence of vascular calcification, osteophytes, scoliosis, or facet joint sclerosis. Such abnormalities may affect only certain vertebrae, in which case appropriate densitometric assessment of the nonaffected vertebrae can be performed, or radiographic criteria (minimum 25% reduction in the height of vertebral bodies) for treatment may be relied upon.
Contra-Indications: Patients with known hypersensitivity to etidronate disodium. Didrocal is also contraindicated for patients with clinically overt osteomalacia; appropriate treatment to resolve their osteomalacia should be initiated before prescribing Didrocal therapy. tag_WarningWarnings
Manufacturers’ Warnings In Clinical States: The cyclic intermittent, 14-day, etidronate disodium dosage of the Didrocal therapy provides an acceptable therapeutic window. Overdosage of etidronate disodium may result in skeletal bone abnormalities or cause nephrotic syndrome (see Overdose: Symptoms and Treatment).
Precautions: The Didrocal cyclic therapy should be considered only for the patient population described under Indications.
Patients on the Didrocal cyclic therapy require regular clinical follow-ups.
General: There is no experience to specifically guide the use of the Didrocal therapy in patients with impaired renal function or a history of kidney stone formation. Etidronate disodium is not metabolized and is excreted intact via the kidney. 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.
Consequently, if patients with impaired renal function or with a history of kidney stone formation are placed on Didrocal therapy, serum and urine calcium and other relevant parameters should be monitored regularly to prevent hypercalcemia or hypercalciuria.
The Didrocal therapy provides intermittent cyclic etidronate disodium 400 mg daily for 14 days followed by elemental calcium for 76 days to support bone formation. Before commencing the therapy, patients’ calcium requirements should be adjusted. It is recommended that the appropriately selected postmenopausal women receive at least 1 500 mg calcium/day from all sources, as well as a daily Vitamin D intake of at least 400 IU. The Didrocal therapy provides 500 mg elemental calcium per day.
Patients with a diagnosis of achlorhydria should take calcium carbonate tablets with food to enhance absorption of calcium.
Drug Interactions: Food in the stomach or upper portions of the small intestine, particularly materials with a high calcium content such as milk, may reduce absorption of the etidronate disodium. Vitamins with mineral supplements such as iron, calcium supplements, laxatives containing magnesium, or antacids containing calcium or aluminum should not be taken within 2 hours before or after dosing etidronate disodium, since these also may reduce the absorption of etidronate disodium and could lead to treatment failure (see Dosage).
A small number of patients in the clinical trials received either thiazide diuretics or intravaginal estrogen while on the regimen. The concomitant use of either of these agents did not interfere with the positive effects of the Didrocal therapy on bone.
The concurrent use of etidronate disodium with warfarin has been associated with isolated reports of patients experiencing increases in their prothrombin time. 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 more closely monitored.
Calcium carbonate may interfere with the absorption of tetracycline given concomitantly.
Pregnancy: Didrocal is not intended for administration to pregnant women. In teratology and developmental toxicity studies conducted in rats and rabbits treated with oral dose levels of up to 100 mg/kg (12 times the human dose), no adverse or teratogenic effects have been observed in the offspring. Etidronate disodium has been shown to cause skeletal abnormalities in rat offspring when given to dams in mid-pregnancy at oral dose levels of 300 mg/kg (35 times the human dose); these effects are thought to be the result of the pharmacological effects of the drug on bone. Other effects on the offspring (including decreased live births) have been observed at dose levels that cause significant toxicity in the parent generation and are 60 to 125 times the human dose. There are no adequate and well-controlled studies in pregnant women.
Lactation: Didrocal is not intended for administration during lactation. It is not known whether etidronate is excreted in human milk; it is excreted in the milk of rats. Because many drugs are excreted in human milk and because of the potential for adverse effects on the skeletons of infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Children: The safety and effectiveness of Didrocal in children have not been established.
Dependence Liability: Not applicable.
Laboratory Tests: Depending on the time elapsed since the last dose of etidronate, the Didrocal therapy may prevent bone-imaging diagnostic agents (e.g., technetium-9mmethylene diphosphonate) used in bones scans, from adhering to bone and thus affect the interpretation of imaging results.
Patients: The patient should adhere to the prescribed regimen. The response to therapy is one of slow onset that continues over time.
A patient’s risk for developing fractures may also be reduced if, subsequent to health care counseling, she consumes adequate dietary calcium, gets enough weight-bearing exercise, and uses proper lifting and fall-avoidance techniques.
Each etidronate disodium tablet should be taken as a single oral dose on an empty stomach with a full glass of water. The calcium carbonate tablet may be taken with food and this is recommended if the patient has achlorhydria (see Dosage).
Adverse Reactions: The overall safety of the Didrocal therapy was evaluated in postmenopausal osteoporotic women enrolled in clinical trials. The 3 pivotal trials were randomized, parallel, double blind, and placebo controlled; 2 of these were multicentre trials conducted in the United States. The most common adverse events reported during the first 2 years of the two U.S. trials are listed in Table I. In general, side effects in patients who received etidronate were comparable to those in patients who received placebo.
In osteoporosis clinical trials, the most common side effects were diarrhea and nausea.
Reactions reported less frequently include flatulence, dyspepsia, abdominal pain, constipation and vomiting. The incidence of these events was comparable to that with placebo. In addition, 4 events, headache, gastritis, leg cramps and arthralgia, occurred with a significantly greater incidence in patients who received Didrocal cyclical therapy compared with those who received placebo. All episodes of leg cramps were transient in nature, most occurred at night, and most required no treatment. All patients with arthralgia reported joint discomfort or pain that was generally mild and related to underlying osteoarthritis.
The numbers of both deaths and withdrawals due to adverse events were similar in the Didrocal and placebo groups.
Postmarketing Experience: Other adverse events that have been reported in postmarketing studies of a number of indications, 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, skin rashes (such as follicular eruption, macular rash, maculopapular rash), pruritus, Stevens-Johnson syndrome, and urticaria; osteomalacia; neuropsychiatric events, including amnesia, confusion, depression, and hallucination; paresthesias; burning tongue; erythema multiforme; and exacerbation of asthma.
In patients receiving etidronate disodium, there have been rare reports of leukopenia, agranulocytosis, and pancytopenia. Also, there have been very rare cases of leukemia reported with etidronate use (1/100 000) in ongoing safety surveillance since 1978 encompassing approximately 1.5 million patient-years of treatment. Any causal relationship to either the treatment or to the patients’ underlying disease has not been established.
Exacerbation of existing peptic ulcer disease with resulting complications has been reported in a few patients.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Clinical experience with acute overdosage of etidronate disodium is extremely limited. Decreases in serum calcium following substantial overdosage may be expected in some patients. Signs and symptoms of hypocalcemia may also occur in some of these patients. Some patients may develop vomiting. An 18-year-old female who ingested an estimated single dose of 4 000 to 6 000 mg (67 to 100 mg/kg) of etidronate disodium was reported to be mildly hypocalcemic (7.52 mg/dL) and to have experienced paresthesia of the fingers. Hypocalcemia resolved 6 hours after lavage and treatment with i.v. calcium gluconate. A 92-year-old female who accidentally received 1 600 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 Effects).
Gastric lavage may remove unabsorbed drug. Standard procedures for treating hypocalcemia, including the administration of Ca+i.v., would be expected to restore physiologic amounts of ionized calcium and to relieve signs and symptoms of hypocalcemia. Such treatment has been effective.
Because of its limited intestinal absorption, overdosage with calcium carbonate is not likely. If mild hypercalcemia were to occur, signs and symptoms could include polydipsia, polyuria, nausea, vomiting, constipation, abdominal pain, muscle weakness and confusion.
Treatment of hypercalcemia includes cessation of all calcium and vitamin D. Supportive measures include rehydration with or without loop diuretics.
Prolonged continuous daily etidronate treatment of doses of 10 to 20 mg/kg/day for greater than 6 months (chronic overdosage) has been reported to cause nephrotic syndrome and fractures.
Dosage And Administration: The Didrocal therapy is a cyclical regimen administered in 90-day cycles. Each cycle provides 14 white 400 mg etidronate disodium tablets to be taken once daily for 14 days, followed by 76 blue calcium carbonate tablets to be taken once daily for the next 76 days. Patients should maintain an adequate nutritional intake, including calcium and vitamin D. Data from placebo-controlled clinical studies show a significant increase in bone mass of 4 to 5% (p
The etidronate disodium tablet portion of the Didrocal therapy should be administered on an empty stomach, 1 tablet/day with a full glass of water. To aid compliance, it is recommended that patients take the therapy at bedtime, at least 2 hours before or after eating. To maximize absorption of etidronate disodium, patients should not take the following within 2 hours of dosing: food, especially food high in calcium, such as milk or milk products; antacids; vitamins with mineral supplements such as iron; calcium supplements; laxatives containing magnesium.
The calcium carbonate tablet portion of the Didrocal therapy may be administered with food and this is recommended for patients with a diagnosis of achlorhydria.
In the clinical studies of Didrocal therapy, serum alkaline phosphatase was shown to decrease 15 to 20% during the first 2 cycles and to maintain the new level with continuing therapy.
The effect of treatment should be assessed by monitoring changes in bone mass. If this is done, then discontinuation of the therapy should be considered if the bone mass does not stabilize or increase after 4 cycles (1 year) of therapy. Patients who attain adequate response to treatment but discontinue treatment for other reasons should be monitored periodically.
Availability And Storage: The Didrocal therapy consists of etidronate disodium administered for 14 days followed by calcium carbonate administered for the next 76 days.
Etidronate Disodium: The first blister card contains a 14-day supply of 14 tablets. Each, white capsule-shaped, unscored tablet, coded “NE1” (engraved on one side and sculptured in an engraved box on the opposite side), contains: etidronate disodium USP 400 mg. Nonmedicinal ingredients: magnesium stearate, microcrystalline cellulose and pregelatinized starch. Lactose-free.
Calcium Carbonate: The remaining 4 blister cards contain a 76-day supply of 76 tablets. Each blue, capsule-shaped, coated tablet, with “NE2” engraved on both sides, contains: elemental calcium 500 mg as calcium carbonate USP 1 250 mg. Nonmedicinal ingredients: edible black ink, FD&C Blue No. 2 Aluminum Lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose 2910, magnesium stearate, polyethylene glycol 3350, polysorbate 80, sodium starch glycolate and titanium dioxide. Lactose-free.
The unit-of-use dispensing system of the Didrocal 90-day therapy consists of patient instructions, a prescription refill reminder card, and the therapy tablets on 5 blister cards. The Didrocal packaging is designed to provide important benefits to patients. The separately blister-packed tablets and the patient instructions help patients to comply with the cyclical regimen. Dispense only in the original packaging to help patients avoid coingestion of calcium carbonate and etidronate disodium, which will interfere with absorption of etidronate. Store at controlled room temperature (15 to 30Â°C) and protect from light and moisture.
DIDROCALÂ® Procter & Gamble Pharmaceuticals Etidronate DisodiumCalcium Carbonate Bone Metabolism Regulator