Pomegara (Concentrate) Instructions for Use

Marketing Authorization Holder

Genfamedica S.A. (Switzerland)

Manufactured By

Omega Laboratories, Ltd. (Canada)

ATC Code

M05BA03 (Pamidronic acid)

Active Substance

Pamidronic acid (Rec.INN registered by WHO)

Dosage Forms

	Pomegara	Concentrate for solution for infusion 60 mg/10 ml: 1 vial.
		Concentrate for solution for infusion 90 mg/10 ml: 1 vial.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a clear, colorless liquid.

Excipients: mannitol, water for injections.

10 ml – vials (1) – cardboard packs.

Concentrate for solution for infusion as a clear, colorless liquid.

Excipients: mannitol, water for injections.

10 ml – vials (1) – cardboard packs.

Clinical-Pharmacological Group

Bone resorption inhibitor for bone metastases

Pharmacotherapeutic Group

Bone resorption inhibitor – bisphosphonate

Pharmacological Action

Pamidronic acid is an inhibitor of osteoclast-mediated bone resorption.

Pamidronic acid forms a stable compound with hydroxyapatite crystals of bone tissue and inhibits the dissolution of these crystals in vitro. It is believed that the inhibition of bone resorption in vivo may, at least partially, be explained by the binding of pamidronic acid to minerals.

Pamidronic acid inhibits the entry of osteoclast precursors into bone tissue and their subsequent transformation into mature osteoclasts responsible for the resorption of this tissue.

In patients with malignant neoplasms, Pamidronic acid suppresses osteolysis and, in the presence of tumor-induced hypercalcemia, reduces serum calcium and phosphorus levels and decreases their excretion, as well as the excretion of hydroxyproline in the urine.

By reducing the severity of hypercalcemia, the drug increases the glomerular filtration rate, which in most patients is accompanied by a decrease in the initially elevated serum creatinine concentration.

Pharmacokinetics

Pamidronic acid has a high affinity for calcified tissues, which are considered the “site of apparent elimination” of pamidronic acid.

After the start of the infusion, the concentration of pamidronic acid in the blood plasma increases rapidly, and after the end of the infusion, it decreases just as quickly. The apparent T_1/2 of pamidronic acid in plasma is about 0.8 hours. Therefore, the equilibrium concentration of pamidronic acid is achieved with an infusion duration of more than 2-3 hours. The accumulation of pamidronic acid in bone tissue is not limited by the volume of this tissue but depends solely on the total dose of the administered drug.

The binding of circulating pamidronic acid to plasma proteins is about 54% and increases if the upper limit of the normal blood calcium concentration is exceeded.

Pamidronic acid is not believed to undergo biotransformation and is excreted almost exclusively by the kidneys. After IV infusion, approximately 20-55% of the administered dose of pamidronic acid is detected in the urine within 72 hours in unchanged form. The remaining amount is retained in the body for an indefinite period. The excretion of pamidronic acid in the urine is biphasic, with apparent T_1/2 of 1.6 and 27 hours, respectively.

In case of impaired liver function, higher mean AUC (39.7%) and C_max (28.6%) were observed. Nevertheless, Pamidronic acid was still rapidly eliminated from the plasma. The drug was not detected in the plasma 12-36 hours after the infusion. Since the drug is used only once a month, accumulation of pamidronic acid does not occur.

In case of significant renal impairment (CrCl<30 ml/min), the mean AUC value increases approximately 3 times. Although the excretion rate of pamidronic acid decreases depending on CrCl, the total amount of pamidronic acid excreted by the kidneys does not change significantly.

Indications

• Hypercalcemia due to malignant tumors;
• Diseases accompanied by increased osteoclast activity: bone metastases of malignant tumors (predominantly osteolytic) and multiple myeloma;
• Paget’s disease of bone.

ICD codes

Dosage Regimen

The drug is administered intravenously as an infusion at a rate not exceeding 1 mg/min.

In adults and elderly patients with hypercalcemia due to malignant tumors, it is recommended to hydrate the patient with 0.9% sodium chloride solution before starting Pomegara or during therapy. The total dose of Pomegara used during the course of treatment depends on the patient’s initial serum calcium level. The table below provides recommendations for selecting the required dose of pamidronic acid depending on serum calcium concentration values.

The total dose of Pomegara can be administered either at one time or as several infusions over 2-4 consecutive days. The maximum course dose of the drug (for both the first and subsequent courses of treatment) is 90 mg. A significant decrease in serum calcium concentration is usually observed 24-48 hours after the administration of pamidronic acid, normalization of this indicator occurs within 3-7 days. If normalization of blood calcium levels is not achieved within the specified time, additional administration of the drug is possible. The duration of the achieved effect varies among individual patients. If hypercalcemia recurs, repeated courses of therapy with pamidronic acid are carried out. With an increase in the number of administration courses, the effectiveness of pamidronic acid may decrease.

For bone metastases of malignant tumors (predominantly osteolytic) and myeloma the recommended dose is 90 mg, once every 4 weeks. In patients with bone metastases of malignant tumors receiving chemotherapy at 3-week intervals, Pomegara at a dose of 90 mg can also be used at 3-week intervals.

For Paget’s disease of bone the recommended total dose of Pomegara for a course of treatment is 180-210 mg. The total dose of the drug, amounting to 180 mg, can be administered either as 6 infusions (30 mg once a week) or as 3 infusions (60 mg once every 2 weeks). If the total dose is expected to be 210 mg, then a dose of 30 mg is recommended for the first administration. This dosage regimen (but without the initial 30 mg dose) can be repeated after 6 months until remission of the disease is achieved or in case of exacerbation.

Pamidronic acid is not recommended for patients with severe renal impairment (CrCl less than 30 ml/min), except in cases of life-threatening hypercalcemia, if the potential benefit of use outweighs the risk of possible complications. In patients with mild (CrCl 61-90 ml/min) or moderate (CrCl 30-60 ml/min) renal impairment, no adjustment of the drug dosage regimen is required. The infusion rate of pamidronic acid in such patients should not exceed 90 mg/4 h (approximately 20-22 mg/h). If symptoms of renal impairment appear, therapy with pamidronic acid should be discontinued until renal function is restored (creatinine concentration exceeding the baseline level by no more than 10%).

For patients with mild and moderate hepatic impairment no adjustment of the drug dosage regimen is required.

Rules for preparing the infusion solution

The contents of the vial should be further diluted before administration with an infusion solution that does not contain calcium (for example, 0.9% sodium chloride solution or 5% dextrose solution) to a concentration not exceeding 90 mg/250 ml.

Adverse Reactions

Adverse reactions when using pamidronic acid are usually mild and temporary. The most common undesirable reactions are asymptomatic hypocalcemia and fever (increase in body temperature by 1-2°C (28.4°F)), usually developing within the first 48 hours after infusion of the drug. Fever usually resolves on its own and does not require treatment.

Criteria for assessing the frequency of adverse events: very common (≥10%), common (from ≥1% to <10%), uncommon (from ≥0.1% to <1%), rare (from ≥0.01% to <0.1%), very rare (<0.001%), including isolated reports.

From the hematopoietic system: common – anemia, thrombocytopenia, lymphocytopenia; very rare – leukopenia.

Allergic reactions: uncommon – allergic reactions, including anaphylactoid reactions, bronchospasm, dyspnea, angioedema; very rare – anaphylactic shock.

From the nervous system: common – paresthesia, tetany (as manifestations of hypocalcemia), headache, insomnia or increased drowsiness; uncommon – convulsions, agitation, dizziness; very rare – confusion, visual hallucinations.

From the senses: common – conjunctivitis; uncommon – uveitis (iritis, iridocyclitis); very rare – scleritis, episcleritis, xanthopsia (seeing objects in yellow).

From the cardiovascular system: common – marked increase in BP; uncommon – marked decrease in BP; very rare – dyspnea, pulmonary edema (as signs of left ventricular failure), edema (as a sign of congestive heart failure) due to fluid overload.

From the digestive system: common – nausea, vomiting, anorexia, abdominal pain, diarrhea, constipation, gastritis; uncommon – dyspepsia.

Dermatological reactions: common – rash; uncommon – itching.

From the musculoskeletal system: common – transient bone pain, joint pain, myalgia; uncommon – muscle spasms.

From the urinary system: uncommon – acute renal failure; rare – focal segmental glomerulosclerosis, including the collapsing variant, nephrotic syndrome; very rare – exacerbation of concomitant kidney diseases, hematuria.

Laboratory parameters very common – hypocalcemia, hypophosphatemia; common – hypokalemia, hypomagnesemia, increased serum creatinine concentration; uncommon – changes in liver function tests, increased serum urea concentration; very rare – hyperkalemia, hypernatremia.

Infections very rare – reactivation of latent viral infections (Herpes simplex, Herpes zoster).

Local reactions: common – pain, redness, swelling, induration, phlebitis, thrombophlebitis at the injection site.

Other: very common – fever and flu-like symptoms, sometimes accompanied by malaise, chills, feeling of tiredness and flushing; very rare – development of osteonecrosis (mainly of the jaw, usually after tooth extraction or other dental intervention). A clear causal relationship for the development of osteonecrosis has not been established.

Contraindications

• Pregnancy (except in cases of life-threatening hypercalcemia);
• Lactation period (breastfeeding);
• Childhood (no experience of use in children);
• Hypersensitivity to pamidronic acid or other bisphosphonates, as well as to other ingredients included in the drug.

Use with caution in patients with impaired renal function.

Use in Pregnancy and Lactation

There is no clinical experience with the use of pamidronic acid in pregnant women. The drug should not be used during pregnancy, except in cases of life-threatening hypercalcemia (experimental studies have not revealed a teratogenic effect of pamidronic acid, nor a negative effect on reproductive function and fertility).

Use in Hepatic Impairment

In case of impaired liver function, higher mean AUC (39.7%) and C_max (28.6%) were observed. Nevertheless, Pamidronic acid was still rapidly eliminated from the plasma. The drug was not detected in the plasma 12-36 hours after the infusion. Since the drug is used only once a month, accumulation of pamidronic acid does not occur. For patients with mild and moderate hepatic impairment no adjustment of the drug dosage regimen is required.

Use in Renal Impairment

Use with caution in patients with impaired renal function.

Pamidronic acid is not recommended for patients with severe renal impairment (CrCl less than 30 ml/min), except in cases of life-threatening hypercalcemia, if the potential benefit of use outweighs the risk of possible complications. In patients with mild (CrCl 61-90 ml/min) or moderate (CrCl 30-60 ml/min) renal impairment, no adjustment of the drug dosage regimen is required. The infusion rate of pamidronic acid in such patients should not exceed 90 mg/4 h (approximately 20-22 mg/h). If symptoms of renal impairment appear, therapy with pamidronic acid should be discontinued until renal function is restored (creatinine concentration exceeding the baseline level by no more than 10%).

Geriatric Use

The drug is prescribed to the elderly according to indications.

Special Precautions

The use of bisphosphonates, including pamidronic acid, may lead to impaired renal function. Due to the risk of developing clinically significant renal impairment, a single dose should not exceed 90 mg, and the recommended dilution norms and drug administration rates should be observed. Usually, Pamidronic acid at a dose of 90 mg in 250 ml of infusion solution is administered over 2 hours. In patients with myeloma and hypercalcemia due to malignant tumors, the dose of pamidronic acid, amounting to 90 mg, is diluted in 500 ml of infusion solution and administered over more than 4 hours.

During treatment, monitoring of renal function (determination of serum creatinine concentrations before each infusion of pamidronic acid), serum electrolyte, calcium and phosphorus concentrations is necessary.

The risk of developing hypocalcemia is increased in patients who have undergone thyroid surgery due to latent hypoparathyroidism.

In patients with heart disease, especially elderly patients, the administration of additional amounts of saline may lead to the appearance or worsening of signs of heart failure. Fever (or flu-like syndrome) may also contribute to the development of this complication.

To reduce the risk of developing hypocalcemia, patients with Paget’s disease of bone, who are at increased risk of calcium and vitamin D deficiency, should be additionally prescribed these drugs orally.

Although the causal relationship of osteonecrosis development with the use of bisphosphonates has not been clearly established, dental interventions should be avoided during therapy with pamidronic acid.

Pamidronic acid should not be used concomitantly with other bisphosphonates, as the consequences of such combined treatment have not been studied.

Effect on ability to drive vehicles and operate machinery

Some side effects of the drug, such as drowsiness and/or dizziness, may negatively affect the ability to drive a car and perform potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

If the recommended doses of the drug are exceeded, careful monitoring of the patient’s condition is necessary. No antidote is known. If clinical signs of hypocalcemia develop (paresthesia, tetany, marked decrease in BP), an infusion of calcium gluconate should be performed.

Drug Interactions

Concomitant use of pamidronic acid with commonly used anticancer agents was not accompanied by any significant interactions.

When used in combination with calcitonin in patients with severe hypercalcemia, a synergistic effect was noted, leading to a faster decrease in serum calcium concentration.

Caution is required when co-administering with other drugs that have nephrotoxic effects.

In patients with myeloma, concomitant use with tolbutamide increases the risk of developing renal impairment.

Pharmaceutical interactions

Pamidronic acid can form complexes with divalent cations and therefore should not be added to IV solutions containing calcium (for example, Ringer’s solution).

Storage Conditions

The drug should be stored out of the reach of children.

Shelf Life

Shelf life – 2 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.