Tevabone (Tablet and capsule kit) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

R.P.SCHERER, GmbH & Co.KG (Germany)

ATC Codes

A11CC03 (Alfacalcidol)

M05BA04 (Alendronic acid)

Active Substances

Alfacalcidol (Rec.INN)

Alendronic acid (Rec.INN)

Dosage Form

Tevabone

Set of tablets and capsules: 70 mg tablet (1 pc.) + 1 mcg capsule (7 pcs.): 4 or 12 envelopes

Dosage Form, Packaging, and Composition

Set of tablets and capsules

Tablets are white or almost white, round, flat, beveled, with an engraving “T” on one side.

Excipients: microcrystalline cellulose – 113.8 mg, croscarmellose sodium – 3 mg, magnesium stearate – 2 mg.

Capsules are soft gelatin, oval, white or almost white, opaque, with the inscription “1.0” in black ink; capsule contents – a pale yellow oily solution.

Excipients: citric acid – 0.015 mg, propyl gallate – 0.02 mg, α-tocopherol – 0.02 mg, ethanol – 1.144 mg, peanut oil – 98.8 mg.

Capsule shell composition: gelatin – 48.27 mg, glycerol 85% – 11.78%, anidrisorb 85/70 (sorbitol 25-40%, sorbitan 20-30%, mannitol 0-6%, higher polyols 12.5-19%, water 15-17%) – 7.88 mg, titanium dioxide (E171) – 0.68 mg.

Composition of black ink A10379 shellac, black iron oxide dye, denatured ethanol (methylated spirit), isopropanol, 1-butanol, ethyl acetate.

1 pc.(tab.) – blisters (1) + 7 pcs.(caps.) – blisters (1) – cardboard envelope (4) – cardboard packs.
1 pc.(tab.) – blisters (1) + 7 pcs.(caps.) – blisters (1) – cardboard envelope (12) – cardboard packs.

Clinical-Pharmacological Group

Combined drug for the treatment of osteoporosis

Pharmacotherapeutic Group

Osteoporosis treatment agent (bone resorption inhibitor + calcium-phosphorus metabolism regulator)

Pharmacological Action

Combined drug for the treatment of osteoporosis.

Alendronic acid, being a bisphosphonate, inhibits the process of active bone resorption caused by osteoclasts, without directly affecting the formation of new bone tissue. Having an affinity for bone hydroxyapatite, Alendronic acid accumulates mainly in areas of its active resorption. The mechanism of action is associated with the suppression of the functional activity and stimulation of apoptosis of osteoclasts. Against the background of therapy with alendronic acid, bone mineralization increases and its qualitative characteristics improve.

Alfacalcidol – a regulator of calcium-phosphorus metabolism, a precursor of the active metabolite of vitamin D₃ – calcitriol. Increases the absorption of calcium and phosphorus in the intestine, increases their reabsorption in the kidneys, restores positive calcium balance in the treatment of calcium malabsorption syndrome, reduces the concentration of parathyroid hormone in the blood. By affecting both parts of the bone remodeling process (resorption and synthesis), Alfacalcidol not only increases bone mineralization but also increases its elasticity by stimulating the synthesis of bone matrix proteins, bone morphogenetic proteins, and bone growth factors. Treatment with alfacalcidol forms bone with a normal histological structure, and the strength of bone tissue increases in all parts of the skeleton.

Alendronic acid and Alfacalcidol increase bone strength, and their effects are synergistic due to different mechanisms of action. The inhibition of catabolic processes in bones by alendronic acid is complemented by the bone anabolic effect of alfacalcidol, leading to the formation of normal bone structure. Due to the pharmacological effects of both substances, their use in combination can reduce the potential risk of developing hypocalcemia, hypercalcemia, and hypercalciuria. A significant reduction in the risk of fractures is achieved not only by increasing bone strength but also due to the extraosseous (pleiotropic) effect of alfacalcidol – an increase in muscle strength and acceleration of muscle reaction speed.

Pharmacokinetics

Alendronic acid

Absorption

When taken orally on an empty stomach in the dose range from 5 to 70 mg directly 2 hours before breakfast, the bioavailability of alendronic acid in women is 0.64%, in men – 0.6%. The bioavailability of alendronic acid decreases by 40% when taken on an empty stomach 1-1.5 hours before breakfast. After consumption of coffee and orange juice, bioavailability decreases by approximately 60%. The concentration of alendronic acid in blood plasma after oral administration at a therapeutic dose is below the possible detection limit (less than 5 ng/ml).

Distribution

The binding of alendronic acid to plasma proteins is about 78%. Alendronic acid is distributed in soft tissues and then rapidly redistributed to bones, where it is fixed, or excreted through the kidneys.

Metabolism and excretion

It does not undergo biotransformation.

Excreted unchanged. The excretion process is characterized by a rapid decrease in the concentration of alendronic acid in blood plasma and an extremely slow release from bones.

Alfacalcidol

Absorption

After oral administration, Alfacalcidol is rapidly absorbed from the gastrointestinal tract. C_max is reached 8-12 hours after a single dose of alfacalcidol. Bioavailability after oral administration is about 100%.

Metabolism

The pharmacological effects of alfacalcidol are realized after its conversion in the body to calcitriol. The conversion of alfacalcidol to calcitriol occurs in the liver by hydroxylation at the 25th carbon atom, and the hydroxylation process occurs very quickly (is substrate-dependent) and does not depend on the functional state of the liver. The maximum concentration of calcitriol in the body is reached 8-12 hours after a single dose of alfacalcidol. Unlike native vitamin D, Alfacalcidol does not require hydroxylation in the kidneys, so it is effective even in patients with reduced activity of renal 1-alpha-hydroxylase (kidney pathology, old age).

Excretion

Calcitriol is excreted by the kidneys and liver in approximately equal proportions, T_1/2 is about 35 hours.

Indications

• Postmenopausal osteoporosis;
• Osteoporosis caused by the use of glucocorticoids.

ICD codes

Dosage Regimen

The drug Tevabone consists of two dosage forms: alendronic acid tablets and alfacalcidol capsules.

To ensure normal absorption and reduce the risk of adverse reactions, the recommendations for use and dosing should be strictly followed.

Alendronic acid

Prescribed orally, 1 tab. (70 mg) once a week, washed down with a glass of water, at least 30 minutes before the first meal, drinks, or other medications. Wash down only with plain water, since other drinks (including mineral water), food, and some medications can reduce the bioavailability of alendronic acid. Tablets should not be chewed or dissolved.

After taking the tablet, the patient must remain in an upright position (standing or sitting) for at least 30 minutes. Do not take the tablet before going to bed or before getting up in the morning.

Elderly patients do not require dose adjustment.

In renal impairment with CrCl > 35 ml/min, no dose adjustment is required.

Alfacalcidol

Prescribed orally, 1 caps. (1 mcg) once/day in the evening daily. Capsules should be swallowed whole with plenty of fluid.

The drug Tevabone is intended for long-term use.

Adverse Reactions

Adverse effects are classified according to the following frequency: very common (≥ 10%); common (≥ 1%, but < 10%); uncommon (≥ 0.1%, but < 1%); rare (≥ 0.01%, but < 0.1%); very rare (< 0.01%, including isolated cases).

When using alendronic acid

Digestive system: common – abdominal pain, dyspepsia, acid regurgitation, diarrhea, dysphagia, flatulence, gastritis, gastric ulcer, esophageal mucosal ulceration; uncommon – nausea, vomiting, constipation, gastritis, esophagitis, esophageal mucosal erosion, melena; rare – esophageal stricture, oropharyngeal mucosal ulceration, esophageal perforation, upper gastrointestinal bleeding (relationship with alendronic acid intake not established).

Musculoskeletal system: common – bone pain, muscle pain, joint pain, muscle cramps; rare – osteonecrosis of the jaw, mainly in cancer patients taking bisphosphonates, but such cases have also been noted in patients undergoing therapy for osteoporosis; unknown frequency – stress fracture of the proximal femur, associated or not associated with trauma.

Metabolism: rare – symptomatic hypocalcemia, usually associated with predisposing conditions, hypophosphatemia.

CNS: common – headache.

Sensory organs: rare – uveitis, scleritis, episcleritis.

Allergic reactions: uncommon – rash, itching, erythema; rare – rash associated with photosensitivity, urticaria, angioedema; very rare – severe skin reactions, including erythema multiforme exudativum (Stevens-Johnson syndrome) and toxic epidermal necrolysis (Lyell’s syndrome).

Other: rare – transient symptoms similar to those in the acute phase of the disease (myalgia, malaise and fever), usually at the beginning of treatment.

When using alfacalcidol

Metabolism: rare – hypercalcemia; very rare – slight increase in HDL concentration in blood plasma. In patients with severe renal impairment, hyperphosphatemia, heterotopic calcifications in the cornea and blood vessels may develop.

Digestive system: uncommon – anorexia, vomiting, heartburn, abdominal pain, nausea, dry mouth, epigastric discomfort, constipation, diarrhea; rare – slight increase in the activity of liver enzymes in plasma (ALT, AST).

CNS: rare – weakness, fatigue, dizziness, drowsiness.

Cardiovascular system: rare – tachycardia.

Musculoskeletal system: uncommon – moderate muscle pain, bone pain, joint pain.

Allergic reactions: rare – skin rash, itching; very rare – anaphylactic shock associated with peanut oil.

Due to the multidirectional influence of alendronic acid and alfacalcidol on the serum calcium concentration, the use of a combination of these drugs avoids sharp fluctuations in serum calcium concentration.

Contraindications

• Conditions leading to delayed passage of food through the esophagus (including esophageal strictures or achalasia);
• Inability of the patient to stand or sit upright for at least 30 minutes;
• Hypocalcemia;
• Hypercalcemia;
• Burnett’s syndrome and/or milk-alkali syndrome (plasma calcium concentrations > 2.6 mmol/l, calcium phosphate > 3.7 mmol/l, pH > 7.44);
• Severe renal impairment (CrCl < 35 ml/min);
• Patients on hemodialysis;
• Hypervitaminosis D;
• Hyperphosphatemia (except for hyperphosphatemia in hypoparathyroidism);
• Hypermagnesemia;
• Sucrase/isomaltase deficiency, fructose intolerance, glucose/galactose malabsorption;
• Childhood;
• Pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to alendronic acid, alfacalcidol and other components of the drug.

With caution, the drug should be prescribed for gastrointestinal diseases in the acute phase, including dysphagia, esophagitis, gastritis, duodenitis, gastric and duodenal ulcer; for hypoparathyroidism, hypovitaminosis D, calcium malabsorption, nephrolithiasis, atherosclerosis, renal impairment (CrCl more than 35 ml/min), chronic heart failure, patients with an increased risk of developing hypercalcemia, including in leukemia, lymphoma, sarcoidosis, pulmonary tuberculosis (active form).

Use in Pregnancy and Lactation

Due to insufficient data on the use of alendronic acid and/or the risk of alfacalcidol overdose, the drug Tevabone is contraindicated during pregnancy and breastfeeding.

Use in Renal Impairment

In renal impairment with CrCl > 35 ml/min, no dose adjustment is required.

Contraindication: severe renal impairment (CrCl < 35 ml/min); patients on hemodialysis

Pediatric Use

Contraindication: childhood.

Geriatric Use

Elderly patients do not require dose adjustment.

Special Precautions

For the use of alendronic acid

Special attention should be paid to any signs of adverse reactions in the esophagus. The patient should be informed about the need to stop taking the drug and consult a doctor if dysphagia, pain when swallowing, chest pain, or the appearance or intensification of heartburn develops.

Due to the existing risk of irritation of the upper gastrointestinal mucosa, as well as aggravation of the underlying disease, caution is recommended when prescribing the drug to patients with gastrointestinal diseases in the acute phase (such as dysphagia, esophagitis, gastritis, duodenitis, gastric and duodenal ulcer), as well as recently suffered (within the previous year) gastrointestinal diseases (gastric and duodenal ulcer, active gastrointestinal bleeding, surgery on the upper gastrointestinal tract, except pyloroplasty).

There are reports of cases of osteonecrosis of the jaw, usually associated with tooth extraction and/or local infection (including osteomyelitis), in cancer patients receiving treatment regimens including bisphosphonates (primarily intravenously). Many of these patients also received chemotherapy and glucocorticoids. There are also reports of osteonecrosis of the jaw in patients with osteoporosis receiving oral bisphosphonates. Before using bisphosphonates, patients with concomitant risk factors (e.g., cancer, chemotherapy, radiation therapy, glucocorticoid therapy, poor oral hygiene) should undergo a dental examination with appropriate preventive dental treatment. Patients undergoing treatment with bisphosphonates should avoid invasive dental procedures if possible. In patients with osteonecrosis of the jaw who are on bisphosphonate therapy, dental surgical interventions may worsen the condition. If surgical interventions are necessary, it should be taken into account that there is no data on the possibility of reducing the risk of osteonecrosis of the jaw after discontinuation of bisphosphonates. Prescriptions and recommendations of the attending physician should be based on an individual assessment of the benefit/risk ratio for each patient.

The time of onset of bone, joint, and muscle pain in patients during therapy with bisphosphonates varied from 1 day to several months after the start of treatment. In most patients, after discontinuation of treatment, the severity of pain decreased; in some patients, pain reappeared when therapy with the same or another bisphosphonate was resumed.

If the patient forgot to take the alendronic acid tablet, it should be taken the next morning. Do not take 2 tablets in one day; you should continue taking 1 tablet once a week on the day that was chosen for taking from the very beginning of treatment.

In patients with hypocalcemia, hypovitaminosis D, and hypoparathyroidism, corrective therapy for mineral metabolism disorders must be carried out before starting treatment with alendronic acid. Due to the positive effect of alendronic acid on bone mineral density during treatment, a slight asymptomatic decrease in the concentration of calcium and phosphorus in the blood serum may be observed. There are isolated reports of symptomatic hypocalcemia, sometimes severe, usually in patients predisposed to it (e.g., with hypoparathyroidism, vitamin D deficiency, calcium malabsorption).

There are reports of the occurrence of stress fractures of the proximal femur during long-term treatment with alendronic acid (from 18 months to 10 years).

Fractures occurred after minimal trauma or without it. In some patients, pain in the proximal part of the thigh first appeared, which persisted for several weeks or even months before this symptom ended with a femoral fracture. Often the fractures were bilateral, so if one femur is fractured, the condition of the other femur must be monitored.

In patients taking alendronic acid, especially with concomitant glucocorticoid therapy, it is extremely important to ensure sufficient intake of calcium and vitamin D with food or in the form of medications.

The absorption of bisphosphonates is significantly reduced when taken simultaneously with food.

For the use of alfacalcidol

Alfacalcidol may enhance hypercalcemia and/or hypercalciuria when prescribed to patients with a disease associated with uncontrolled overproduction of calcitriol (e.g., leukemia, lymphoma, sarcoidosis), and may also enhance hyperphosphatemia. If the plasma calcium concentration is more than 2.6 mmol/l, the intake of other calcium-containing drugs should be excluded. If there is no effect, the intake of alfacalcidol capsules should be stopped until the serum calcium concentration normalizes (2.2-2.6 mmol/l). Control of calcium and phosphate concentrations in the blood is carried out before treatment with alfacalcidol and, if necessary, corrective therapy is carried out.

During treatment with alfacalcidol, the concentration of electrolytes is determined once a week at the beginning, upon reaching C_max and throughout the entire treatment period – every 3-5 weeks, and alkaline phosphatase activity is also monitored (in case of impaired renal function (creatinine clearance more than 35 ml/min) – weekly monitoring).

Peanut oil in rare cases can cause severe allergic reactions.

Patients with hereditary fructose intolerance or fructose malabsorption should not be prescribed the Tevabone drug, since the kit includes alfacalcidol capsules containing sorbitol.

Effect on the ability to drive vehicles and mechanisms

Due to the possibility of developing side effects from the central nervous system during treatment, caution must be exercised when driving vehicles, as well as when engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Alendronic acid

Symptoms: hypocalcemia, hypophosphatemia, diarrhea, heartburn, esophagitis, erosive and ulcerative lesions of the gastrointestinal mucosa are possible.

Treatment: administration of milk or an antacid to bind alendronic acid. Due to the risk of esophageal irritation, vomiting should not be induced. The patient should be in an upright position.

Alfacalcidol

Early symptoms of hypervitaminosis D (caused by hypercalcemia): diarrhea, constipation, nausea, vomiting, dry mouth, anorexia, metallic taste in the mouth, hypercalciuria, polyuria, polydipsia, pollakiuria/nocturia, headache, fatigue, general weakness, myalgia, bone pain.

Late symptoms of hypervitaminosis D: dizziness, confusion, drowsiness, heart rhythm disturbance, skin itching, increased blood pressure, conjunctival hyperemia, nephrolithiasis, weight loss, photophobia, pancreatitis, gastralgia; rarely – changes in psyche and mood.

Symptoms of chronic vitamin D intoxication: calcification of soft tissues, blood vessels and internal organs (kidneys, lungs), renal failure, cardiovascular failure, growth impairment in children.

Treatment: discontinue the drug. In the early stages of acute overdose, the administration of mineral oil may have a positive effect (which helps reduce absorption and increase the excretion of alfacalcidol in the feces). In severe cases, hydration with infusion of saline solutions is carried out, “loop” diuretics, corticosteroids, bisphosphonates, calcitonin are prescribed, and hemodialysis using solutions with low calcium content is performed. The content of electrolytes in the blood, renal and cardiac function (according to ECG) should be monitored, especially in patients receiving digoxin. There is no specific antidote.

Drug Interactions

Concomitant administration with food, calcium-containing beverages (including mineral water), dietary supplements, antacids and other oral medications may impair the absorption of alendronic acid. Therefore, the interval between taking alendronic acid and other oral drugs should be at least 30 minutes.

Combined use of alendronic acid (but not simultaneous administration) with estrogen preparations is not accompanied by a change in their action or the development of side effects.

Oral administration of prednisone is not accompanied by clinically significant changes in the bioavailability of alendronic acid.

Corticosteroids enhance the side effects of alendronic acid on the gastrointestinal tract.

With the simultaneous use of alfacalcidol with cardiac glycosides, the risk of arrhythmia increases.

Inducers of liver microsomal enzymes (including phenytoin and phenobarbital) reduce, and inhibitors increase the plasma concentration of alfacalcidol (a change in its effectiveness is possible).

The absorption of alfacalcidol is reduced when used concomitantly with mineral oil (for a long time), cholestyramine, colestipol, sucralfate, antacids, and albumin-based drugs.

In this regard, alfacalcidol capsules should not be taken simultaneously with aluminum-containing antacids; the interval between taking these medications should be at least 2 hours.

Taking antacids increases the risk of hypermagnesemia and hyperaluminemia. The toxic effect is weakened by retinol, tocopherol, ascorbic acid, pantothenic acid, thiamine, riboflavin.

In perimenopausal women, the effect of alfacalcidol may be enhanced by estrogens. Calcitonin, derivatives of etidronic and pamidronic acids, plicamycin and corticosteroids reduce the effect of alfacalcidol.

Alfacalcidol increases the absorption of phosphorus-containing drugs and the risk of hyperphosphatemia.

Concomitant use of alfacalcidol with calcium preparations and thiazide diuretics can cause hypercalcemia, due to increased absorption of calcium in the intestine and increased its reabsorption in the kidneys.

During therapy with alfacalcidol, other vitamin D medicines and its derivatives should not be prescribed due to possible additive interaction and an increased risk of hypercalcemia.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.