Etidronate and Calcium (Didrocal) - Uses, Dose, Side effects, MOA

Etidronate and Calcium (Didrocal) is a combination of a bisphosphonate (etidronate) and calcium. It is used in the treatment of postmenopausal and corticosteroid-induced osteoporosis.

Etidronate and Calcium (Didrocal) Uses:

Note: This is not approved in the US.

Corticosteroid-induced osteoporosis:
- Prevention of corticosteroid-induced osteoporosis
Postmenopausal osteoporosis:
- It is used for the treatment and prevention of established postmenopausal osteoporosis.

Etidronate and Calcium (Didrocal) Dose in Adults

Note:

3-months treatment (90 days) regimen involves sequential administration of two products within the packaging; not to be taken concurrently.
The first blister card contains white tablets containing etidronate disodium, while the remaining four blister cards contain blue, capsule-shaped tablets containing calcium carbonate.
Consider discontinuation of treatment if a bone mass is not stabilized within 4 cycles (1 year) of therapy.

Etidronate and Calcium (Didrocal) Dose in the treatment of Corticosteroid-induced osteoporosis and postmenopausal osteoporosis:

Oral: Etidronate disodium 400 mg for 14 days once a day, followed by calcium carbonate 1,250 mg (500 mg elemental calcium) for 76 days once a day.

Use in Children:

Not indicated.

Etidronate and Calcium Pregnancy Category: C

In some studies on animal reproduction, adverse events were reported.
You can contact individual agents.
According to the manufacturer, this product was not designed for pregnant women.

Use of etidronate or calcium during lactation:

Calcium is excreted into breast milk (refer to calcium carbonate monograph for additional information); excretion of etidronate is not known.
Manufacturer recommends that you decide whether to stop nursing or discontinue using the drug.
This is taking into consideration the importance of mother's treatment due to the possibility of serious adverse reactions in the infant.
This product is not for nursing women.

Dose in Kidney Disease:

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and monitor closely. The IV form of etidronate has been noted to be nephrotoxic.

Dose in Liver disease:

The manufacturer’s labeling doesn't provide any dosage adjustments.

Side Effects of Etidronate and Calcium (Didrocal):

Central Nervous System:
- Dizziness
- Headache
Gastrointestinal:
- Diarrhea
- Nausea
- Flatulence
- Constipation
- Dyspepsia
- Vomiting

Contraindications to Etidronate and Calcium (Didrocal):

Hypersensitivity to etidronate diodium or any other component of the formulation
Clinically-overt osteomalacia is a condition that can be treated with etidronate/calcium carbate therapy.

Warnings and precautions

Bone fractures:
- The subtrochanteric and diaphyseal fractures are located below the hip joint.
- Patients who have received bisphosphonates to prevent osteoporosis treatment/treatment have had atypical femur fractures.
- Prodromal pain can occur weeks or even months before the fracture occurs.
- Although most of these fractures have been reported in bisphosphonate-treated patients, it is not clear if this is the cause.
- A femur fracture should be considered for patients who present with groin or thigh pain and have had bisphosphonates in the past.
- Long-term therapy that lasts more than three to five years may increase the risk for patients with osteoporosis.
- However, the relative benefits of therapy are generally greater than the absolute risk of AFF in the initial 5 years.
- Patients who have a fracture of the femoral shaft should be stopped from receiving bisphosphonate therapy; check for fractures in the contralateral leg.
Muscle, joint, or bone pain
- Pain can occur in a matter of hours or days.
- Recurrences were reported by some patients who tried to retake the drug or another bisphosphonate.
- Patients with these symptoms or those who have had bisphosphonate therapy in the past should not use it.
- Patients with severe symptoms should consider quitting therapy. Symptoms usually disappear once treatment is stopped.
- Bisphosphonate treatment can sometimes cause severe, debilitating, or even fatal, bone, joint, and/or muscular pain.
Diarrhea:
- Diarrhea can occur with therapy. If the dosage is higher, it may be more frequent.
- Patients with GI diseases prone to diarrhea, such as Crohn disease, ulcerative Colitis and Irritable Bowel Syndrome, should be cautious.
Irritation of the gastrointestinal mucosa
- Patients with esophageal disease or gastritis, dysphagia, gastritis or ulcers should be cautious. This could worsen the underlying condition.
- Stop using the medication if you experience any new or worsening symptoms.
- Oral bisphosphonates have been linked to irritation of the upper gastrointestinal mucosa, esophagitis and dysphagia.
- Patients who are unable to follow dosing instructions run the risk of becoming more dangerous.
Hypocalcemia:
- Hypocalcemia must be corrected before therapy can begin. Make sure you get enough vitamin D and calcium from all sources.
- Bisphosphonates have been linked to hypocalcemia.
Ocular effects
- Bisphosphonates have been shown to cause conjunctivitis and uveitis as well as iritis, scleritis, episcleritis, and scleritis.
- Patients suffering from severe or complicated inflammation may need to stop therapy and should be referred to an ophthalmologist.
Osteonecrosis in the jaw:
- A diagnosis of cancer, radiotherapy or concomitant chemotherapy, corticosteroids, anemia, infection or preexisting dental diseases are all risk factors.
- Bisphosphonate therapy has been linked to osteonecrosis in the jaw (ONJ), also known as medication-related osteonecrosis (MRONJ)
- MRONJ is most commonly seen after dental procedures, such as tooth extractions, and in patients who receive intravenous bisphosphonates for cancer.
- However, it has also been seen in patients with osteoporosis postmenopausal and other patients who are receiving oral bisphosphonates.
- MRONJ risk increases with intravenous antiresorptive treatment. However, the risk of MRONJ is lower with oral bisphosphonate therapy that lasts more than 4 years.
- According to the manufacturer's label, preventive dentistry and dental exams should be done before placing patients at risk (eg, cancer, immune suppression or poor hygiene) on chronic bisphosphonate treatment.
- A position paper from the American Association of Maxillofacial Surgeons states that MRONJ was associated with bisphosphonate (denosumab) and other antiresorptive drugs (denosumab) and antiangiogenic (eg bevacizumab and sunitinib), used to treat osteoporosis and malignancy.
- MRONJ risk is significantly higher for cancer patients who receive antiresorptive treatment than patients who receive osteoporosis therapy (regardless how much medication they are taking or what dosing schedule they are on).
- If possible, avoid invasive dental procedures during treatment.
- Patients who require dental treatment should not discontinue bisphosphonates. Clinical judgment is the best guide.
- AAOMS suggests that there is no evidence to suggest that stopping oral bisphosphonate treatment after a tooth is extracted increases the risk of ONJ. It also indicates that patients who have been receiving oral bisphosphonate for less than 4 years and have not developed any clinical risk factors should undergo no delay or alternations in any procedure. Special considerations are required for patients receiving dental implant therapy.
- Patients who have been taking oral bisphosphonates more than 4years or patients who have taken antiangiogenic or corticosteroids concomitantly for oral bisphosphonates less than 4years should consider a 60-day (2-month) drug-free time before undergoing invasive dental procedures. This recommendation is based on theoretical benefits.
- An oral surgeon should be consulted for patients who develop ONJ from therapy.
Renal impairment
- Patients with impaired renal function should be cautious.
- If treatment is started, serum and urinary calcium should be closely monitored.

Etidronate and calcium: Drug Interaction

Risk Factor C (Monitor therapy)
Aminoglycosides	May enhance the hypocalcemic effect of Bisphosphonate Derivatives.
Amphetamines	Antacids may decrease the excretion of Amphetamines.
Angiogenesis Inhibitors (Systemic)	May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased.
Antipsychotic Agents (Phenothiazines)	Antacids may decrease the absorption of Antipsychotic Agents (Phenothiazines).
Bromperidol	Antacids may decrease the absorption of Bromperidol.
Calcium Channel Blockers	Calcium Salts may diminish the therapeutic effect of Calcium Channel Blockers.
Captopril	Antacids may decrease the serum concentration of Captopril.
Cardiac Glycosides	Calcium Salts may enhance the arrhythmogenic effect of Cardiac Glycosides.
Cefpodoxime	Antacids may decrease the serum concentration of Cefpodoxime.
Cysteamine (Systemic)	Antacids may diminish the therapeutic effect of Cysteamine (Systemic).
Deferasirox	Bisphosphonate Derivatives may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.
Dexmethylphenidate	Antacids may increase the absorption of Dexmethylphenidate. Specifically, antacids may interfere with the normal release of drug from the extended-release capsules (Focalin XR brand), which could result in both increased absorption (early) and decreased delayed absorption.
Diacerein	Antacids may decrease the absorption of Diacerein.
DOBUTamine	Calcium Salts may diminish the therapeutic effect of DOBUTamine.
Methylphenidate	Antacids may increase the absorption of Methylphenidate. Specifically, antacids may interfere with the normal release of drug from the extended-release capsules (Ritalin LA brand), which could result in both increased absorption (early) and decreased delayed absorption.
Nonsteroidal Anti-Inflammatory Agents	May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern.
Proton Pump Inhibitors	May diminish the therapeutic effect of Bisphosphonate Derivatives.
QuiNIDine	Antacids may decrease the excretion of QuiNIDine.
Rosuvastatin	Antacids may decrease the serum concentration of Rosuvastatin.
	Thiazide and Thiazide-Like Diuretics: May decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis.
Vitamin D Analogs	Calcium Salts may enhance the adverse/toxic effect of Vitamin D Analogs.
Risk Factor D (Consider therapy modification)
Acalabrutinib	Antacids may decrease the serum concentration of Acalabrutinib. Management: Separate administration of acalabrutinib from the administration of any antacids by at least 2 hours in order to minimize the potential for a significant interaction.
Allopurinol	Antacids may decrease the absorption of Allopurinol.
Alpha-Lipoic Acid	Calcium Salts may decrease the absorption of Alpha-Lipoic Acid. Alpha-Lipoic Acid may decrease the absorption of Calcium Salts.
Atazanavir	Antacids may decrease the absorption of Atazanavir.
Bictegravir	Calcium Salts may decrease the serum concentration of Bictegravir. Management: Bictegravir, emtricitabine, and tenofovir alafenamide can be administered with calcium salts under fed conditions, but coadministration with or 2 hours after a caclium salt is not recommended under fasting conditions.
Bisacodyl	Antacids may diminish the therapeutic effect of Bisacodyl. Antacids may cause the delayed-release bisacodyl tablets to release drug prior to reaching the large intestine. Gastric irritation and/or cramps may occur.
Bismuth Subcitrate	Antacids may diminish the therapeutic effect of Bismuth Subcitrate. Management: Avoid administration of antacids within 30 minutes of bismuth subcitrate (tripotassium bismuth dicitrate) administration.
Bisphosphonate Derivatives	Polyvalent Cation Containing Products may decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral medications containing polyvalent cations within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Exceptions: Pamidronate; Zoledronic Acid.
Bosutinib	Antacids may decrease the serum concentration of Bosutinib. Management: Administer antacids more than 2 hours before or after bosutinib.
Calcium Polystyrene Sulfonate	Antacids may enhance the adverse/toxic effect of Calcium Polystyrene Sulfonate. The combined use of these two agents may result in metabolic alkalosis and/or loss of efficacy of the cation exchange resin. Management: To minimize this interaction, consider: a)separating doses by 2 or more hours; b)rectal administration of the exchange resin; or c)alternatives to antacids. Monitor for metabolic alkalosis and attenuation of CPS effects. Avoid magnesium hydroxide.
Cefditoren	Antacids may decrease the serum concentration of Cefditoren. Management: Concomitant use of cefditoren with antacids is not recommended. Consider alternative methods to control acid reflux (eg, diet modification) or alternative antimicrobial therapy. If antacid therapy can not be avoided, separate dosing by several hours.
Cefuroxime	Antacids may decrease the serum concentration of Cefuroxime. Management: Administer cefuroxime axetil at least 1 hour before or 2 hours after the administration of shortacting antacids.
Chloroquine	Antacids may decrease the serum concentration of Chloroquine. Management: Separate administration of antacids and chloroquine by at least 4 hours to minimize any potential negative impact of antacids on chloroquine bioavailability.
Corticosteroids (Oral)	Antacids may decrease the bioavailability of Corticosteroids (Oral). Management: Consider separating doses by 2 or more hours. Budesonide enteric coated tablets could dissolve prematurely if given with drugs that lower gastric acid, with unknown impact on budesonide therapeutic effects.
Dabigatran Etexilate	Antacids may decrease the serum concentration of Dabigatran Etexilate. Management: Dabigatran etexilate Canadian product labeling recommends avoiding concomitant use with antacids for 24 hours after surgery. In other situations, administer dabigatran etexilate 2 hours prior to antacids. Monitor clinical response to dabigatran therapy.
Dasatinib	Antacids may decrease the serum concentration of Dasatinib. Management: Simultaneous administration of dasatinib and antacids should be avoided. Administer antacids 2 hours before or 2 hours after dasatinib.
Deferiprone	Polyvalent Cation Containing Products may decrease the serum concentration of Deferiprone. Management: Separate administration of deferiprone and oral medications or supplements that contain polyvalent cations by at least 4 hours.
Delavirdine	Antacids may decrease the serum concentration of Delavirdine. Management: Separate doses of delavirdine and antacids by at least 1 hour. Monitor for decreased delavirdine therapeutic effects with this combination.
Dolutegravir	Calcium Salts may decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral calcium. Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after oral calcium salts. Alternatively, dolutegravir and oral calcium can be taken together with food.
Eltrombopag	Polyvalent Cation Containing Products may decrease the serum concentration of Eltrombopag. Management: Administer eltrombopag at least 2 hours before or 4 hours after oral administration of any polyvalent cation containing product.
Elvitegravir	Antacids may decrease the serum concentration of Elvitegravir. Management: Separate administration of antacids and elvitegravir-containing products by at least 2 hours in order to minimize the risk for an interaction.
Erdafitinib	Serum Phosphate Level-Altering Agents may diminish the therapeutic effect of Erdafitinib. Management: Avoid coadministration of serum phosphate level-altering agents with erdafitinib before initial dose increase period based on serum phosphate levels (Days 14 to 21).
Erlotinib	Antacids may decrease the serum concentration of Erlotinib. Management: Separate the administration of erlotinib and any antacid by several hours in order to minimize the risk of a significant interaction.
Estramustine	Calcium Salts may decrease the absorption of Estramustine.
Fosinopril	Antacids may decrease the serum concentration of Fosinopril. Management: The US and Canadian fosinopril manufacturer labels recommend separating the doses of antacids and fosinopril by 2 hours.
Gefitinib	Antacids may decrease the serum concentration of Gefitinib. Management: Administer gefitinib at least 6 hours before or after administration of an antacid, and closely monitor clinical response to gefitinib.
Hyoscyamine	Antacids may decrease the serum concentration of Hyoscyamine. Management: Administer immediate release hyoscyamine before meals and antacids after meals when these agents are given in combination.
Salts	Iron Antacids may decrease the absorption of Iron Salts. Exceptions: Ferric Carboxymaltose; Ferric Citrate; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Isomaltoside; Iron Sucrose.
Itraconazole	Antacids may increase the serum concentration of Itraconazole. Antacids may decrease the serum concentration of Itraconazole. Management: Administer Sporanox brand itraconazole at least 2 hours before or 2 hours after administration of any antacids. Exposure to Tolsura brand itraconazole may be increased by antacids; consider itraconazole dose reduction.
Ketoconazole (Systemic)	Antacids may decrease the serum concentration of Ketoconazole (Systemic). Management: Administer oral ketoconazole at least 2 hours prior to use of any antacid product. Monitor patients closely for signs of inadequate clinical response to ketoconazole.
Lanthanum	Antacids may diminish the therapeutic effect of Lanthanum.
Ledipasvir	Antacids may decrease the serum concentration of Ledipasvir. Management: Separate the administration of ledipasvir and antacids by 4 hours.
Mesalamine	Antacids may diminish the therapeutic effect of Mesalamine. Antacid-mediated increases in gastrointestinal pH may cause the premature release of mesalamine from specific sustained-release mesalamine products. Management: Avoid concurrent administration of antacids with sustained-release mesalamine products. Separating antacid and mesalamine administration, and/or using lower antacid doses may be adequate means of avoiding this interaction.
Methenamine	Antacids may diminish the therapeutic effect of Methenamine.
Multivitamins/Fluoride (with ADE)	May increase the serum concentration of Calcium Salts. Calcium Salts may decrease the serum concentration of Multivitamins/Fluoride (with ADE). More specifically, calcium salts may impair the absorption of fluoride. Management: Avoid eating or drinking dairy products or consuming vitamins or supplements with calcium salts one hour before or after of the administration of fluoride.
Multivitamins/Minerals (with ADEK, Folate, Iron)	Antacids may decrease the serum concentration of Multivitamins/Minerals (with ADEK, Folate, Iron). Specifically, antacids may decrease the absorption of orally administered iron. Management: Separate dosing of oral ironcontaining multivitamin preparations and antacids by as much time as possible in order to minimize impact on therapeutic efficacy of the iron preparation.
Mycophenolate	Antacids may decrease the absorption of Mycophenolate. Management: Separate doses of mycophenolate and antacids by at least 2 hours. Monitor for reduced effects of mycophenolate if taken concomitant with antacids.
Neratinib	Antacids may decrease the serum concentration of Neratinib. Specifically, antacids may reduce neratinib absorption. Management: Separate the administration of neratinib and antacids by giving neratinib at least 3 hours after the antacid.
Nilotinib	Antacids may decrease the serum concentration of Nilotinib. Management: Separate the administration of nilotinib and any antacid by at least 2 hours whenever possible in order to minimize the risk of a significant interaction.
PAZOPanib	Antacids may decrease the serum concentration of PAZOPanib. Management: Avoid the use of antacids in combination with pazopanib whenever possible. Separate doses by several hours if antacid treatment is considered necessary. The impact of dose separation has not been investigated.
PenicillAMINE	Polyvalent Cation Containing Products may decrease the serum concentration of PenicillAMINE. Management: Separate the administration of penicillamine and oral polyvalent cation containing products by at least 1 hour.
Phosphate Supplements	Antacids may decrease the absorption of Phosphate Supplements. Management: This applies only to oral phosphate administration. Separating administer of oral phosphate supplements from antacid administration by as long as possible may minimize the interaction. Exceptions: Sodium Glycerophosphate Pentahydrate.
Phosphate Supplements	Calcium Salts may decrease the absorption of Phosphate Supplements. Management: This applies only to oral phosphate and calcium administration. Administering oral phosphate supplements as far apart from the administration of an oral calcium salt as possible may be able to minimize the significance of the interaction. Exceptions: Sodium Glycerophosphate Pentahydrate.
Polyvalent Cation Containing Products	May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral medications containing polyvalent cations within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate.
Potassium Phosphate	Antacids may decrease the serum concentration of Potassium Phosphate. Management: Consider separating administration of antacids and oral potassium phosphate by at least 2 hours to decrease risk of a significant interaction.
Quinolones	Antacids may decrease the absorption of Quinolones. Of concern only with oral administration of quinolones. Management: Avoid concurrent administration of quinolones and antacids to minimize the impact of this interaction. Recommendations for optimal dose separation vary by specific quinolone. Exceptions: LevoFLOXacin (Oral Inhalation).
Quinolones	Calcium Salts may decrease the absorption of Quinolones. Of concern only with oral administration of both agents. Exceptions: LevoFLOXacin (Oral Inhalation); Moxifloxacin (Systemic).
Raltegravir	Calcium Carbonate may decrease the serum concentration of Raltegravir.
Rilpivirine	Antacids may decrease the serum concentration of Rilpivirine. Management: Administer antacids at least 2 hours before or 4 hours after rilpivirine. Administer antacids at least 6 hours before or 4 hours after the rilpivirine/dolutegravir combination product.
Riociguat	Antacids may decrease the serum concentration of Riociguat. Management: Separate the administration of antacids and riociguat by at least 1 hour in order to minimize any potential interaction.
Sodium Polystyrene Sulfonate	Antacids may enhance the adverse/toxic effect of Sodium Polystyrene Sulfonate. The combined use of these two agents may result in metabolic alkalosis and/or loss of efficacy of the exchange resin. Management: To minimize this interaction, consider: a)separating doses by 2 or more hours; b)rectal administration of the exchange resin; or c)alternatives to antacids. Monitor for metabolic alkalosis and attenuation of SPS effects. Avoid magnesium hydroxide.
Sotalol	Antacids may decrease the serum concentration of Sotalol. Management: Avoid simultaneous administration of sotalol and antacids. Administer antacids 2 hours after sotalol.
Strontium Ranelate	Calcium Salts may decrease the serum concentration of Strontium Ranelate. Management: Separate administration of strontium ranelate and oral calcium salts by at least 2 hours in order to minimize this interaction.
Sulpiride	Antacids may decrease the serum concentration of Sulpiride. Management: Separate administration of antacids and sulpiride by at least 2 hours in order to minimize the impact of antacids on sulpiride absorption.
Tetracyclines	Antacids may decrease the absorption of Tetracyclines. Management: Separate administration of antacids and oral tetracycline derivatives by several hours when possible to minimize the extent of this potential interaction. Exceptions: Eravacycline.
Tetracyclines	Calcium Salts may decrease the serum concentration of Tetracyclines. Management: If coadministration of oral calcium with oral tetracyclines can not be avoided, consider separating administration of each agent by several hours. Exceptions: Eravacycline.
Thyroid Products	Calcium Salts may diminish the therapeutic effect of Thyroid Products. Management: Separate the doses of the thyroid product and the oral calcium supplement by at least 4 hours.
Trientine	Polyvalent Cation Containing Products may decrease the serum concentration of Trientine. Management: Avoid concomitant administration of trientine and oral products that contain polyvalent cations. If oral iron supplements are required, separate the administration by 2 hours. If other oral polyvalent cations are needed, separate administration by 1 hour.
Velpatasvir	Antacids may decrease the serum concentration of Velpatasvir. Management: Separate administration of velpatasvir and antacids by at least 4 hours.
Risk Factor X (Avoid combination)
Baloxavir Marboxil	Polyvalent Cation Containing Products may decrease the serum concentration of Baloxavir Marboxil.
Calcium Acetate	Calcium Salts may enhance the adverse/toxic effect of Calcium Acetate.

Monitoring parameters:

Bone mineral density (BMD) should be evaluated 1 to 2 years after initiating therapy and every 1 to 2 years (or less frequently if stable) thereafter;
Serum and urine calcium (particularly in renal impairment or a history of nephrolithiasis);
Serum 25(OH)D and phosphorous;
Dental exam and preventive dentistry prior to initiation of therapy for patients at risk for osteonecrosis (eg, cancer patients, immunosuppressed, and head/neck radiotherapy)

How to administer Etidronate and Calcium (Didrocal)?

Oral:

Administer etidronate tablets with a full glass of water, 2 hours before or after meals on an empty stomach (preferably at bedtime).
The calcium carbonate tablets may be administered with food (recommended in patients with achlorhydria).