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DRUGS & SUPPLEMENTS
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Difosfen tablets, USP contain either 200 mg or 400 mg of Difosfen, the disodium salt of (1-hydroxyethylidene) diphosphonic acid, for oral administration. This compound, also known as EHDP, regulates bone metabolism. Difosfen, USP is a white powder, highly soluble in water, with a molecular weight of 250 and the following structural formula:
Inactive ingredients: Each tablet contains magnesium stearate, microcrystalline cellulose, pregelatinized starch and starch (corn).
Difosfen 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.
Difosfen is not metabolized. The amount of drug absorbed after an oral dose is approximately 3%. In normal subjects, plasma half-life 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 Difosfen does not cross the blood-brain barrier.
Difosfen therapy does not adversely affect serum levels of parathyroid hormone or calcium.
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.
Difosfen 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 Difosfen therapy.
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 Difosfen in heterotopic ossification following total hip replacement or due to spinal cord injury.
Difosfen 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 Difosfen prevents or retards heterotopic ossification. There is no evidence Difosfen affects mature heterotopic bone.
Difosfen tablets, USP are 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. Difosfen tablets are not approved for the treatment of osteoporosis.
Difosfen tablets are indicated for the treatment of symptomatic Paget’s disease of bone. Difosfen therapy usually arrests or significantly impedes the disease process as evidenced by:
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 one year following cessation of therapy. The upper limit of this period has not been determined.
The effects of the Difosfen treatment in patients with asymptomatic Paget’s disease have not been studied. However, Difosfen treatment of such patients may be warranted if extensive involvement threatens irreversible neurologic damage, major joints, or major weight-bearing bones.
Difosfen tablets are indicated in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury.
Difosfen tablets reduce the incidence of clinically important heterotopic bone by about two-thirds. Among those patients who form heterotopic bone, Difosfen tablets retard the progression of immature lesions and reduces the severity by at least half. Follow-up data (at least 9 months post-therapy) suggests these benefits persist.
In total hip replacement patients, Difosfen tablets do not promote loosening of the prosthesis or impede trochanteric reattachment.
In spinal cord injury patients, Difosfen tablets do not inhibit fracture healing or stabilization of the spine.
Difosfen, 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 etidronate disodium is given to patients with active upper gastrointestinal problems.
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 etidronate disodium 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 to 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. In patients who cannot comply with dosing instructions due to mental disability, therapy with etidronate disodium 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.
In Paget’s patients the response to therapy may be of slow onset and continue for months after Difosfen therapy is discontinued. Dosage should not be increased prematurely. A 90-day drug-free interval should be provided between courses of therapy.
No specific warnings.
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.
Difosfen 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 post therapy. There is no experience to specifically guide treatment in patients with impaired renal function. Difosfen 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 Difosfen I.V. infusion, for hypercalcemia of malignancy, occasional, mild-to-moderate abnormalities in renal function were observed during or immediately after treatment.
Difosfen 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 post therapy. In patients with fractures, especially of long bones, it may be advisable to delay or interrupt treatment until callus is evident.
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 etidronate sodium. 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, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.
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.
In post-marketing experience, there have been infrequent reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates. 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.
In Paget’s patients, treatment regimens exceeding the recommended 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 Difosfen therapy, may be especially prone to fracture.
Patients with predominantly lytic lesions should be monitored radiographically and biochemically to permit termination of Difosfen in those patients unresponsive to treatment.
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.
Long-term studies in rats have indicated that Difosfen is not carcinogenic.
In teratology and developmental toxicity studies conducted in rats and rabbits treated with dosages of up to 100 mg/kg, no adverse or teratogenic effects have been observed in the offspring. Difosfen 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 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 vs. oral) on this risk has not been studied.
There are no adequate and well controlled studies in pregnant women. Difosfen should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 Difosfen is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established. Pediatric patients have been treated with Difosfen, 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.
Clinical studies of Difosfen 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, Difosfen dosage should be reduced when reductions in glomerular filtration rates are present. In addition, patients with renal impairment should be closely monitored.
The incidence of gastrointestinal complaints is the same for Difosfen 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.
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 (vs. 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.
No specific adverse reactions.
The worldwide post-marketing experience for Difosfen reflects its use in the following approved
Indications: Paget’s disease, heterotopic ossification, and hypercalcemia of malignancy. It also reflects the use of Difosfen for osteoporosis where approved in countries outside the US. Other adverse events that have been reported and were thought to be possibly related to Difosfen 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, toxic epidermal necrolysis, and urticaria; osteomalacia; neuropsychiatric events, including amnesia, confusion, depression, and hallucination; and paresthesias.
In patients receiving Difosfen, 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.
Clinical experience with acute Difosfen 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 mg to 6000 mg (67 to 100 mg/kg) of Difosfen 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 Difosfen per day for 3.5 days experienced marked diarrhea and required treatment for electrolyte imbalance. Orally administered Difosfen may cause hematologic abnormalities in some patients.
Difosfen 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 post therapy.
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.
Difosfen tablets should be taken as a single, oral dose. As with other bisphosphonates, it is recommended that Difosfen tablets should be swallowed with a full glass of water. 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 2 hours of dosing:
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 or reduce elevated cardiac output. Doses in excess of 20 mg/kg/day are not recommended.
Retreatment should be initiated only after 1) an etidronate disodium-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.
The following treatment regimens have been shown to be effective:
Retreatment has not been studied.
Difosfen Tablets, USP are available containing 200 mg or 400 mg of Difosfen, USP.
The 200 mg tablets are white, rectangular-shaped tablets with ED 200 on one side and G on the other side. They are available as follows:
NDC 0378-3286-91
bottles of 60
The 400 mg tablets are white, capsule-shaped tablets with ED 400 on one side and G on the other side. They are available as follows:
NDC 0378-3288-91
bottles of 60
Store at 20° to 25°C (68° to 77°F).
Avoid excessive heat (over 104°F or 40°C).
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
Manufactured by:
ALPHAPHARM PTY LTD
15 Garnet Street
Carole Park QLD 4300
Australia
ALP:ETDN:R8
Revised: 3/2017
PRINCIPAL DISPLAY PANEL - 200 mg
NDC 0378-3286-91
Etidronate
Disodium
Tablets, USP
200 mg
Rx only 60 Tablets
Each tablet contains:
Difosfen, USP 200 mg
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Keep this and all medication
out of the reach of children.
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Avoid excessive heat (over 104°F
or 40°C).
Usual
Dosage: See accompanying
prescribing information.
Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
Made in Australia
3290/0
RM3286D4
PRINCIPAL DISPLAY PANEL - 400 mg
NDC 0378-3288-91
Etidronate
Disodium
Tablets, USP
400 mg
Rx only 60 Tablets
Each tablet contains:
Difosfen, USP 400 mg
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Keep this and all medication
out of the reach of children.
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Avoid excessive heat (over 104°F
or 40°C).
Usual
Dosage: See accompanying
prescribing information.
Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
Made in Australia
3291/0
RM3288D4
Depending on the reaction of the Difosfen after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Difosfen not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Difosfen addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology