Preotact (Powder) Instructions for Use

Marketing Authorization Holder

Nycomed Danmark, ApS (Denmark)

Manufactured By

Vetter Pharma-Fertigung, GmbH & Co. KG (Germany)

Labeled By

NYCOMED DANMARK, ApS (Denmark)

ATC Code

H05AA03 (Parathyroid hormone)

Active Substance

Parathyroid hormone (Rec.INN registered by WHO)

Dosage Form

Preotact

Powder for solution for subcutaneous administration 100 mcg/dose: cartridges 2 or 6 pcs.

Dosage Form, Packaging, and Composition

Powder for preparation of solution for subcutaneous administration in the form of a white or almost white porous solid substance or powder.

Excipients: sodium chloride 4.5 mg, mannitol 30 mg, citric acid monohydrate 1.26 mg, hydrochloric acid to pH 5.5, sodium hydroxide to pH 5.5.

Composition of the diluent solution: water for injections up to 1.13 g, m-cresol 3.62 mg.

1.61 mg (100 mcg/dose) – cartridges (2) two-chamber – cardboard packs.
1.61 mg (100 mcg/dose) – cartridges (6) two-chamber – cardboard packs.

Clinical-Pharmacological Group

Parathyroid hormone analogue

Pharmacotherapeutic Group

Parathyroid agent

Pharmacological Action

Preotact contains recombinant human Parathyroid hormone (PTH), which is identical to the natural polypeptide consisting of 84 amino acid residues.

The physiological action of PTH includes stimulation of bone tissue formation through direct action on bone-forming cells (osteoblasts), indirectly increasing calcium absorption in the intestine and calcium reabsorption in the renal tubules, as well as increasing phosphate excretion by the kidneys.

The effect of PTH on bone tissue depends on its systemic concentration. A temporary increase in PTH concentration after subcutaneous administration of Preotact stimulates the formation of new bone tissue on trabecular and tubular (periosteal and/or endosteal) bone surfaces due to predominant stimulation of osteoblastic activity compared to osteoclastic activity.

PTH is the main regulator of plasma calcium concentration homeostasis. After subcutaneous administration of Preotact (100 mcg), the total plasma calcium concentration gradually increases and reaches a maximum concentration approximately 6-8 hours after injection. Plasma calcium concentration returns to baseline 24 hours after drug dose administration.

Pharmacokinetics

Absorption

After subcutaneous administration of 100 mcg PTH in the abdominal area, a rapid rise in its plasma concentration occurs, which reaches a maximum 1-2 hours after administration. The mean half-life is approximately 1.5 hours. The absolute bioavailability of 100 mcg PTH after subcutaneous administration in the abdominal area is 55%.

Distribution

The volume of distribution at steady state after intravenous administration of the drug is approximately 5.4 liters. Individual differences in the volume of distribution of the drug are approximately 40%.

Biotransformation

PTH is effectively cleared from the blood through a receptor-mediated process occurring in the liver, where it is metabolized to form smaller peptide fragments. Fragments from N-terminal molecules are further metabolized intracellularly, while fragments from C-terminal molecules are secreted back into the blood and then excreted by the kidneys. After subcutaneous administration of a dose of Preotact, the content of circulating C-terminal molecules in the blood is 60-90%.

The systemic clearance of PTH (45.3 L/hour) after an intravenous dose of the drug is close to the normal plasma flow in the liver and corresponds to increased hepatic metabolism of the active substance. Individual differences in systemic clearance are approximately 15%.

Elimination

PTH is metabolized in the liver and to a lesser extent in the kidneys. PTH is not excreted from the body in its native form. Circulating C-terminal molecules are filtered by the kidneys but are subsequently broken down into even smaller fragments during tubular reabsorption.

Elderly patients

No differences in the pharmacokinetics of Preotact depending on age (from 47 to 88 years) were identified. Dose adjustment depending on age is not required.

Gender differences

The drug was studied only in postmenopausal women.

Indications

• Treatment of osteoporosis in postmenopausal women at high risk of fractures.

ICD codes

Dosage Regimen

The drug is prescribed once a day at the recommended dose of 100 mcg as a subcutaneous injection into the abdominal area.

The drug is administered using the Preotact pen-injector. The contents of the two-chamber cartridge are mixed in the pen-injector. After dilution, the liquid should be clear and colorless. Shaking the drug is not allowed, as this may lead to denaturation of the active substance. If the diluted solution is opaque, colored, or contains undissolved particles, the cartridge should be removed from the pen-injector and a new one installed.

The patient should be trained in injection technique. The user manual containing information on injection technique is supplied with the Preotact pen-injector.

If dietary intake of calcium and vitamin D is insufficient, these substances should be prescribed additionally.

The duration of treatment with Preotact is up to 24 months.

To further increase bone mineral density after therapy with the drug, patients may be prescribed bisphosphonate therapy.

Special patient groups

Renal impairment

In patients with mild or moderate renal failure (creatinine clearance from 30 to 80 ml/min), dose adjustment is not required.

Hepatic impairment

In patients with mild or moderate hepatic impairment (total Child-Pugh score from 7 to 9), dose adjustment is not required.

Children and adolescents

The safety and efficacy of Preotact in patients under 18 years of age have not been studied. The drug is not recommended for use in children and young adult patients.

Elderly patients

Dose adjustment of the drug depending on age is not required.

Adverse Reactions

The following categories were used to classify side effects by frequency of occurrence: very common (>1/10); common (> 1/100 and <1/10); uncommon (>1/1000 and <1/100); rare (>1/10000 and <1/1000); very rare (<1/10000), including reports of individual cases.

Infections and infestations

Uncommon: common cold.

Metabolism and nutrition disorders

Very common: hypercalcemia (is transient and mainly appears in the first three months of therapy);

Common: increased blood calcium;

Uncommon: increased blood alkaline phosphatase, anorexia, increased blood uric acid.

Nervous system disorders

Common: headache, dizziness;

Uncommon: dysgeusia, parosmia.

Cardiac disorders

Common: palpitations.

Gastrointestinal disorders

Very common: nausea;

Common: vomiting, constipation, dyspepsia, diarrhea.

Uncommon: abdominal pain.

Musculoskeletal and connective tissue disorders

Common: muscle cramps, limb pain, back pain.

Renal and urinary disorders

Very common: hypercalciuria;

Common: increased urine calcium/creatinine ratio, increased urine calcium.

General disorders and administration site conditions

Common: injection site hyperemia, weakness, asthenia;

Uncommon: injection site irritation.

Contraindications

• Hypersensitivity to PTH or any of the excipients included in the drug;
• Prior radiation therapy to the skeleton;
• Prior hypercalcemia and other disorders of phosphorus-calcium metabolism;
• Metabolic bone diseases other than primary osteoporosis (including hyperparathyroidism and Paget’s disease);
• Unexplained increase in bone-specific alkaline phosphatase;
• Severe renal failure;
• Severe hepatic failure.

With caution in patients with active or prior urolithiasis.

Use in Pregnancy and Lactation

PTH should not be used during pregnancy and breastfeeding.

Use in Hepatic Impairment

In patients with mild or moderate hepatic impairment (total Child-Pugh score from 7 to 9), dose adjustment is not required.

Use in Renal Impairment

In patients with mild or moderate renal failure (creatinine clearance from 30 to 80 ml/min), dose adjustment is not required.

Pediatric Use

The safety and efficacy of Preotact in patients under 18 years of age have not been studied. The drug is not recommended for use in children and young adult patients.

Geriatric Use

Dose adjustment of the drug depending on age is not required.

Special Precautions

In patients undergoing therapy with Preotact, plasma and/or urine calcium concentration should be monitored after 1, 3, and 6 months of therapy.

Further monitoring (after 6 months) is not recommended for patients whose these parameters were within normal limits during the previous six months of therapy.

Since the increase in plasma calcium concentration reaches a maximum between 6-8 hours after drug administration and returns to baseline after 20-24 hours, patient blood samples for determining plasma calcium concentration should be taken no earlier than 20 hours after the last injection.

Actions in case of increased plasma calcium concentration

Patients with a persistent increase in plasma calcium concentration (above the upper limit of normal) should be checked for the possible presence of a concomitant disease that may be the cause of hypercalcemia (for example, hyperparathyroidism). In the absence of such a disease, the following measures should be taken sequentially:

• Discontinuation of drugs containing calcium and vitamin D;
• Change in the frequency of Preotact administration: 100 mcg every other day;
• If after these measures the plasma calcium concentration remains elevated, the use of Preotact should be suspended and the patient should be monitored until the indicator normalizes.

In patients with a history of hypercalcemia and/or hypercalciuria, the drug may cause an increase in plasma and urine calcium concentration. The use of the drug for more than 24 months is not recommended.

Preotact contains m-cresol, which can cause allergic reactions. One dose of the drug contains less than 1 mmol of sodium ions (23 mg).

Effect on ability to drive vehicles and operate machinery

Since the drug may cause dizziness, patients should refrain from driving vehicles and operating machinery until the symptoms of dizziness cease.

Overdose

In case of drug overdose, prolonged hypercalcemia, nausea, vomiting, dizziness, and headache may occur.

There is no specific antidote for Preotact. Therapy for overdose should include temporary withdrawal of the drug, monitoring of plasma calcium levels, as well as a set of measures aimed at body hydration. Due to the relatively short duration of the drug’s pharmacological activity, additional measures are not required.

Drug Interactions

PTH is a natural peptide that is not metabolized by liver microsomal enzymes (e.g., cytochrome P450 isoenzymes) that metabolize drugs and does not inhibit them.

Moreover, PTH does not bind to plasma proteins and has a small volume of distribution. Consequently, interactions with other drugs are not expected, and special studies on interactions with other drugs have not been conducted. During clinical studies, no cases of interaction with other drugs were identified.

Concomitant use of Preotact and cardiac glycosides in the event of hypercalcemia may lead to the development of glycoside intoxication.

Storage Conditions

Powder and solvent at a temperature not exceeding 25°C (77°F) in a place protected from light. Do not freeze.

Solution for subcutaneous administration do not shake; store in the refrigerator at a temperature of 2°C (35.6°F)-8°C (17.6°F). Do not freeze. store at a temperature up to 25°C (77°F) for 7 days. Keep out of reach of children.

Shelf Life

Shelf life – powder and solvent: 30 months; solution for subcutaneous administration: – 28 days at a temperature of 2°C (35.6°F)-8°C (17.6°F); 7 days at a temperature up to 25°C (77°F).

Dispensing Status

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.