Orotate

Uses

Kit contains 1 tablet of Ibandronic Acid 150 mg and 60 tablets of Calcium Orotate 400 mg. Each box contains one Kit. Each Kit contains 1 film coated tablet of Ibandronate Monosodium Monohydrate equivalent to Ibandronic Acid 150 mg and 60 film coated tablets of Calcium Orotate 400 mg in one calendar strip.

This is used for the treatment and prevention of osteoporosis in women after menopause. It increases bone mineral density (BMD) and reduces the incidence of vertebral fractures.

Orotate is also used to associated treatment for these conditions: Bone Metastases, Hypercalcemia of Malignancy, Osteoporosis

How Orotate works

Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis. Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act.

Osteoclasts mediate resorption of bone. When osteoclasts bind to bone they form podosomes, ring structures of F-actin. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption.

Nitrogen containing bisphosphonates such as ibandronate are known to induce apoptosis of hematopoietic tumor cells by inhibiting the components of the mevalonate pathway farnesyl diphosphate synthase, farnesyl diphosphate, and geranylgeranyl diphosphate. These components are essential for post-translational prenylation of GTP-binding proteins like Rap1. The lack of prenylation of these proteins interferes with their function, and in the case of Rap1, leads to apoptosis. ibandronate also activated caspase-3 which contribute to apoptosis.

Dosage

Orotate dosage

One tablet of Ibandronic Acid 150 mg once monthly on the same date of each month is recommended. To maximize clinical benefit of Ibandronic acid, two tablets of Calcium Orotate 400 mg per day are usually recommended in divided dosage or as directed by physician

To maximize absorption and clinical benefit, Ibandronic Acid tablet of Ibandronic Acid + Calcium Orotate should be taken at least 60 minutes before the first food or drink (other than water) of the day or before taking any oral medication or supplementation, including calcium, antacids, or vitamins.To maximize absorption and clinical benefit, Ibandronic Acid tablet of Ibandronic Acid + Calcium Orotate should be taken at least 60 minutes before the first food or drink (other than water) of the day or before taking any oral medication or supplementation, including calcium, antacids, or vitamins.

To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, Ibandronic Acid tablet should be swallowed whole with a full glass of plain water (250 ml) while the patient is standing or sitting in an upright position. Patients should not lie down for 60 minutes after taking Ibandronic Acid tablet.

Patients should not eat, drink anything except water, or take other medications for at least 60 minutes after taking Ibandronic Acid tablet.

Plain water is the only drink that should be taken with Ibandronic Acid tablet. Note that some mineral waters may have a higher concentration of calcium and therefore should not be used.Patients should not chew, crush or let the tablet dissolve in mouths because of a potential for oropharyngeal ulceration.

Ibandronic Acid 150 mg tablet of Ibandronic Acid + Calcium Orotate should be taken on the same date of each month (i.e., the patient's Ibandronic Acid day).

The patient must not take two Ibandronic Acid 150 mg tablets within the same week.

If the once-monthly dose is missed, and the patient’s next scheduled Ibandronic acid day is more than 7 days away, the patient should be instructed to take one Ibandronic Acid 150 mg tablet in the morning following the date that it is remembered. The patient should then return to taking one Ibandronic Acid 150 mg tablet every month in the morning of their chosen day, according to their original schedule.

If the once-monthly dose is missed, and the patient’s next scheduled Ibandronic Acid day is only 1 to 7 days away, the patient must wait until the subsequent month’s scheduled Ibandronic Acid day to take their tablet. The patient should then return to taking one Ibandronic Acid 150 mg tablet every month in the morning of their chosen day, according to their original schedule.

Start taking Calcium Orotate tablets from the next day of Ibandronic Acid Day (from 'Day 2' and onwards).

Recommendations tor Calcium Supplementation: Patients should receive supplemental calcium (already provided as Calcium Orotate 400 mg tablet) if dietary intake is inadequate.

Side Effects

Ibandronic Acid: Common side effects include Hypertension, Dyspepsia, Nausea, Diarrhea, Abdominal Pain, Arthralgia, Back Pain, Localized Osteoarthritis, Myalgia, Muscle Cramp, Influenza, Nasopharyngitis, Bronchitis, Urinary Tract Infection, Upper Respiratory Tract Infection, Headache, Dizziness, Skin rash, Insomnia etc.

Calcium Orotate: Bloating and swelling in the abdomen are common side effects of Calcium Orotate. Loss of appetite, upset stomach, constipation, nausea, vomiting, unusual weight loss, mood changes, bone/muscle pain, headache, increased thirst/urination, weakness, unusual tiredness, formation of kidney stones may occur infrequently.

Toxicity

Patients experiencing an overdose may present with hypocalcemia, hypophosphatemia, upset stomach, dyspepsia, esophagitis, and uclers. Oral overdose can be managed by giving patients milk or antacids to bind excess unabsorbed ibandronate. Overdoses can be managed by providing intravenous electrolytes and dialysis is not expected to remove excess drug from serum.

Precaution

Ibandronic Acid-

• Upper Gastrointestinal Adverse Reactions: Ibandronic acid of Ibandronic Acid + Calcium Orotate 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 Ibandronic acid is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers). 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 (250 ml) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. 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.
• Hypocalcemia and Mineral Metabolism: Adequate intake of calcium is important in all patients to prevent hypocalcemia.
• Musculoskeletal pain: Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking Ibandronic Acid. Consider discontinuing use if severe symptoms develop.
• Severe Renal Impairment: Ibandronic acid is not recommended for use in patients with severe renal impairment (creatinine clearance of <30 ml/min).

Calcium Orotate-

• Before taking Calcium Orotate, precaution is needed if the patient has any allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Precaution is needed before using this product in kidney disease, kidney stones, little or no stomach acid (achlorhydria), heart disease, disease of the pancreas, sarcoidosis (a certain lung disease), difficulty absorbing nutrition from food (malabsorption syndrome).

Interaction

Ibandronic Acid-

• Calcium Supplements/Antacids: Products containing calcium and other multivalent cations (such as aluminum, magnesium, iron) are likely to interfere with absorption of Ibandronic Acid. Ibandronic Acid should be taken at least 60 minutes before any oral medications, including medications containing multivalent cations (such as antacids, supplements or vitamins). Also, patients should wait at least 60 minutes after dosing before taking any other oral medications.
• Aspirin/Nonstemidal Anti-Inflammatory Drugs (NSAIDs): Because aspirin, NSAIDs, and bisphosphonates are all associated with gastrointestinal irritation, caution should be exercised in the concomitant use of aspirin or NSAIDs with Ibandronic Acid.
• H2 Blockers: In healthy volunteers, co-administration with ranitidine resulted in a 20% increased bioavailability of Ibandronic Acid, which was not considered to be clinically relevant.

Calcium Orotate-

• Calcium can decrease absorption of the following drugs when taken together: biphosphonates (e.g., alendronate), quinolone antibiotics (e.g., ciprofloxacin, levofloxacin), and tetracycline antibiotics (e.g., doxycycline, minocycline), levothyroxine, phenytoin (an anticonvulsant), and tiludronate disodium (to treat Paget's disease). Thiazide-type diuretics can interact with Calcium supplements, increasing the risks of hypercalcemia and hypercalciuria. Both Aluminum and Magnesium-containing antacids increase urinary Calcium excretion. Mineral oil and stimulant laxatives decrease Calcium absorption. Glucocorticoids, such as prednisone, can cause Calcium depletion and eventually osteoporosis when they are used for months. Oral contraceptives as well as estrogen compounds reduce Calcium. Anti-inflammatories such as NSAIDs, Aspirin, Ibuprafen deplete Calcium. Corticosteroids deplete Calcium.

Volume of Distribution

The apparent terminal volume of distribution of ibandronate is 90-368L in headlthy subjects and 103L in postmenopausal women with osteopenia.

Elimination Route

Oral ibandronate is 0.63% bioavailable. In a study of healthy males, a 10mg oral dose had a T_max of 1.1±0.6h and a C_max of 4.1±2.6ng/mL. The T_max is approximately 1 hour, while C_max varies depending on dose.

A 2mg intravenous dose of ibandronate has an AUC of 316ng*h/mL, a 4mg intravenous dose of ibandronate has an AUC of 581ng*h/mL, and a 6mg intravenous dose of ibandronate has an AUC of 908ng*h/mL.

Half Life

The half life of ibandronate in postmenopausal women ranges from 37-157 hours.

Clearance

The total clearance of ibandronate is 84-160mL/min.

Elimination Route

Ibandronate is predominantly eliminated in the urine and the unabsorbed drug is eliminated unchanged in the feces.

Pregnancy & Breastfeeding use

Pregnancy: There are no adequate and well-controlled studies in pregnant women. This should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus. Pregnancy Category of Ibandronic Acid is C.

Nursing Mothers: It is not known whether Ibandronic Acid + Calcium Orotate is excreted in human milk. Caution should be exercised when this is administered to a nursing woman.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Contraindication

Ibandronic Acid is contraindicated in conditions like:

• Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia.
• Inability to stand or sit upright for at least 60 minutes.
• Hypocalcemia.
• Known hypersensitivity to Ibandronic Acid.

Calcium Orotate is contraindicated in conditions like:

• Incomplete or infrequent bowel movements.
• Kidney stone, kidney disease.
• Sarcoidosis.
• Increased activity of the parathyroid gland.
• Extreme loss of body water.

Special Warning

Pediatric use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Patients: No dose adjustment is necessary in the elderly.

Patients with Hepatic Impairment: No dose adjustment is necessary.

Patients with Renal Impairment: No dose adjustment is necessary for patients with mild or moderate renal impairment where creatinine clearance is equal to or greater than 30 ml/min.

Acute Overdose

No specific information is available on the treatment of overdose with ibandronic acid. However, oral overdose may result in hypocalcemia, hypophosphatemia, upset stomach, dyspepsia, esophagitis, gastritis. Milk or antacids should be given to bind Ibandronic Acid

Storage Condition

Keep in a cool and dry place. Protect from light. Keep out of the reach of children.

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