Synthetic salmon calcitonin.
The active substance is synthetic salmon calcitonin (INN name calcitonin). One International Unit (= IU) corresponds to about 0.2 micrograms of synthetic salmon calcitonin.
One metered dose delivers 200 IU of synthetic salmon calcitonin.
Excipients/Inactive ingredients: Benzalkonium chloride, sodium chloride, hydrochloric acid (for pH adjustment) and water (purified).
Pharmacology: Pharmacodynamics: Mechanism of Action: All calcitonin structures consist of 32 amino acids in a single chain with a ring of seven amino-acid residues at the N-terminus that differs in sequence from species to species. Salmon calcitonin is more potent and longer acting than calcitonins from mammalian species due to its greater affinity for receptor binding sites.
By inhibiting osteoclast activity via its specific receptors, salmon calcitonin markedly reduces bone turnover to a normal level in conditions with an increased rate of bone resorption such as osteoporosis. Salmon calcitonin has also been shown both in animal models and in humans to have analgesic activity, probably primarily via a direct effect on the central nervous system.
Miacalcic produces a clinically relevant biological response in humans after only a single dose, as shown by an increase in the urinary excretion of calcium, phosphorus and sodium (by reducing their tubular re-uptake) and a decrease in the urinary excretion of hydroxyproline. Long-term administration of parenteral Miacalcic or Miacalcic nasal spray (up to 5 years of treatment) significantly suppresses biochemical markers of bone turnover such as serum C-telopeptides (sCTX) (for nasal spray only), pyridinoline-crosslinks (for injection only) and skeletal isoenzymes of alkaline phosphatase.
Administration of Miacalcic nasal spray 200 IU/day results in a statistically and clinically significant 36% decrease in the risk of developing new vertebral fractures relative to treatment with vitamin D and calcium alone (placebo). Additionally, the incidence of multiple new vertebral fractures is reduced by 35%, also compared to "placebo".
Calcitonin reduces gastric and exocrine pancreatic secretion.
Miacalcic Nasal Spray results in a statistically significant 1.0-2.0% increase in lumbar spine bone mineral density (BMD), which is evident from year 1 and is sustained for up to 5 years. Hip BMD is preserved.
Pharmacokinetics: The bioavailability of Miacalcic Nasal Spray relative to parenteral administration is between 3 and 5%. Miacalcic is absorbed rapidly through the nasal mucosa and peak plasma concentrations are attained within the first hour of administration (median about 10 minutes). The half-life of elimination has been calculated to be around 20 minutes and no evidence of accumulation was observed with multiple dosing. Doses higher than the recommended dose result in higher blood levels (as shown by an increase in AUC) but relative bioavailability does not increase. As is the case with other polypeptide hormones, there is very little value in monitoring plasma levels of salmon calcitonin since these are not directly predictive of the therapeutic response. Hence, Miacalcic activity should be evaluated by using clinical parameters of efficacy.
Toxicology: Non-Clinical Safety Data: Conventional long-term toxicity, reproduction, mutagenicity and carcinogenicity studies have been performed in laboratory animals.
Minor effects in toxicity studies are attributable to the pharmacological action of salmon calcitonin. Salmon calcitonin is devoid of embryotoxic, teratogenic and mutagenic potential. Toxicity and carcinogenicity studies have shown that salmon calcitonin increases the incidence of pituitary tumors in rats at exposures lower than those likely from clinical use. However, further preclinical studies, particularly a mouse carcinogenicity study, in which the maximum exposure was more than 7,000 times greater than that in humans following a dose of 200 IU, suggested that pituitary tumor induction is specific to the rat.
Furthermore, there have been no reports of adverse events relating to pituitary tumors in patients
There is therefore enough evidence to conclude that pituitary tumor induction is a rat-specific event and that rat pituitary tumors have no relevance for the clinical use of Miacalcic.
Daily intranasal administration for 26 weeks of a placebo containing 0.01% benzalkonium chloride or of high doses of a calcitonin formulation containing 0.01% benzalkonium chloride was well tolerated by monkeys. No treatment-related changes to the respiratory tract were observed. Dogs receiving salmon calcitonin with 0.01% benzalkonium chloride daily by intranasal administration for 4 weeks did not reveal any relevant abnormal findings in the nasal cavity and upper respiratory tract. Miacalcic Nasal Spray with 0.01% benzalkonium chloride did not change the nasal ciliary beat frequency of guinea-pigs or of Pagetic patients over 4 weeks and 6 months of treatment, respectively.
Clinical data including for patients treated for up to 24 months in a study with matched controls, failed to show any pituitary-related changes. In addition, calcitonin receptors in the human pituitary have been shown to be very few in number or even to be completely absent.
Miacalcic Nasal Spray is indicated for the treatment of: Bone pain associated with osteolysis and/or osteopenia.
Paget's bone disease (osteitis deformans) only in patients who do not respond to alternative treatments or for whom such treatments are not suitable.
Neurodystrophic disorders (synonymous with algodystrophy or Sudeck's disease) caused by various etiological and predisposing factors eg, posttraumatic painful osteoporosis, reflex dystrophy, shoulder-arm syndrome, causalgia, drug-induced neurotrophic disorders.
Due to the association between occurrence of malignancies and long-term calcitonin use (see Precautions), the treatment duration in all indications should be limited to the shortest period of time possible and using the lowest effective dose.
Bone pain associated with osteolysis and/or osteopenia: Dosage should be adjusted to the individual patient's needs.
It may take several days of treatment until the analgesic effect is fully developed. For continuing therapy, the initial daily dosage can usually be reduced and/or the interval between administrations prolonged.
In bone pain associated with osteolysis and/or osteopenia the recommended dose is 200-400 IU daily. Up to 200 IU may be administered as a single dose; in cases where a higher dosage is required, it should be given in divided doses.
Paget's Disease: Dosage should be adjusted to the individual patient's needs. Treatment should be discontinued once the patient has responded and symptoms have resolved. Duration of treatment should not normally exceed 3 months due to the association of the increased risk of malignancies with long-term calcitonin use. Under exceptional circumstances, e.g., in patients with impending pathologic fracture, treatment duration may be extended up to a recommended maximum of 6 months.
Treatment markedly reduces serum alkaline phosphatase and urinary hydroxyproline excretion, often to normal levels. However, in rare cases, alkaline phosphatase and hydroxyproline excretion levels may rise after an initial fall; the physician must then judge from the clinical picture whether treatment should be discontinued and when it may be resumed.
Disorders of bone metabolism may recur one or several months after treatment has been discontinued, necessitating a new course of Miacalcic therapy.
In Paget's disease the recommended dose is 200 IU daily in a single dose or in divided doses. In some cases 400 IU in divided doses maybe necessary at the beginning of therapy.
Neurodystrophic disorders: Early diagnosis of neurodystrophic disorders is essential and treatment should start as soon as the diagnosis is confirmed.
The recommended dose is 200 IU daily in a single dose over a period of 2 to 4 weeks. An additional 200 IU may be administered every second day for up to 6 weeks depending on clinical progress.
Special Populations: Renal Impairment: There is no evidence of reduced tolerance or altered dosage requirements of Miacalcic in patients with renal impairment, although no formal studies have been carried out in this specific patient population.
Hepatic Impairment: There is no evidence of reduced tolerance or altered dosage requirements of Miacalcic in patients with hepatic impairment, although no formal studies have been carried out in this specific patient population.
Paediatric patients (below 18 years of age): There is limited experience with the use of Miacalcic in children, therefore no recommendations can be given for this patient population.
Geriatric patients (65 years of age and above): Extensive experience with the use of parenteral Miacalcic in the elderly has shown no evidence of reduced tolerance or altered dosage requirements.
Nausea, vomiting, flushing and dizziness are known to be dose-dependent when Miacalcic is administered parenterally.
Treatment would be symptomatic.
Such events might, therefore, also be expected to occur in association with an overdose of Miacalcic Nasal Spray. However, Miacalcic Nasal Spray has been administered at up to 1600 IU as a single dose and up to 800 IU per day for three days without causing any serious adverse event. Isolated cases of overdose have been reported.
Hypersensitivity to synthetic salmon calcitonin or to any of the excipients (see Description, Precautions and Adverse Reactions).
Allergic reactions: Because salmon calcitonin is a peptide, the possibility of systemic allergic reactions exists and allergic-type reactions including single cases of anaphylactic shock have been reported in patients receiving Miacalcic. Skin testing with diluted sterile solution from Miacalcic ampoules should be considered prior to treatment with Miacalcic in patients with suspected sensitivity to salmon calcitonin.
Risk of Malignancy: Meta-analyses of randomized, controlled trials conducted in patients with osteoarthritis and osteoporosis have shown that long term calcitonin use is associated with a small but statistically significant increase in the incidence of malignancies compared to placebo (see Adverse Reactions). The meta-analyses demonstrated an increase in the absolute rate of occurrence of malignancies for patients treated with calcitonin compared to placebo which varied between 0.7% and 2.36%. Numerical imbalances between calcitonin and placebo were observed after 6 to 12 months of therapy. A mechanism for this observation has not been identified. Patients in these trials were treated with oral or intranasal formulations, however, it cannot be excluded that an increased risk also applies when calcitonin is administered long-term subcutaneous, intramuscular or intravenous. The benefits for the individual patient should be carefully evaluated against possible risks (see Adverse Reactions).
Effects on the Ability to Drive and Use Machines: No studies exist on the effects of Miacalcic on the ability to drive and use machines. Miacalcic may cause fatigue, dizziness and visual disturbances (see Adverse Reactions), which may impair the patient's reactions. Patients must therefore be warned that these effects may occur, in which case they should not drive or use machines.
Women of childbearing potential: There are no data to support special recommendations for women of child-bearing potential.
Pregnancy: Since there is insufficient documented experience with Miacalcic Nasal Spray in pregnant women, Miacalcic should not be administered to such patients. Animal studies have, however, shown that Miacalcic is devoid of embryotoxic and teratogenic potential.
Breast-feeding: Since there is insufficient documented experience with Miacalcic in nursing mothers and it is not known whether salmon calcitonin is excreted into human milk, breast-feeding during treatment is not recommended.
Fertility: There are no data regarding a potential influence of Miacalcic on human fertility.
Tabulated summary of Adverse Drug Reactions:
Adverse drug reactions from multiple sources including clinical trials and post-marketing experience (Table 1) listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (frequency cannot be estimated from the available data).
Click on icon to see table/diagram/image
Local adverse events are generally mild (in about 80% of reports) and require discontinuation of the treatment in less than 5% of cases.
Description of selected adverse reactions: Malignancies:
Meta-analyses of randomized controlled trials conducted in patients with osteoarthritis and osteoporosis have shown that long-term calcitonin use is associated with a small but statistically significant increase in the incidence of malignancies compared to patients treated with placebo. A mechanism for this observation has not been identified (see Precautions).
Concomitant use of calcitonin and lithium may lead to a reduction in plasma lithium concentrations. The dose of lithium may need to be adjusted.
Instructions for Use and Handling: The pump must be primed before first use: Pull up the protective cap, holding the bottle in an upright position, press down the upper part until it clicks. Repeat twice. After the first time the dose counter window shows white and red lines, after the second time white, and after the third time green. It is now ready for use. (See detailed information as follows.)
Information for Patients: When and How to Use Miacalcic Nasal Spray: For administration into the nostrils only.
The patient should switch between each nostril every time use Miacalcic Nasal Spray is used. The pharmacist has stored it in a refrigerator. Before the patient starts using it, let the spray reach room temperature.
Instructions for use/handling of Miacalcic Nasal Spray: Please read the instructions carefully so that the patient knows how to use the patient's nasal spray.
These instructions tell the patient about: The different parts of the nasal spray; How to prepare a new nasal spray for use; Using the nasal spray.
If the spray mechanism should become blocked, this may be resolved by pressing down firmly on the pump; do not attempt to unblock it by using a sharp pointed object as this may cause damage.
If the patient thinks the nasal spray is not working properly, take it back to the pharmacist. The patient should never try to fix the nasal spray or take it apart, as this may affect the dose.
Always follow the doctor's instructions regarding dosage carefully.
Keep this leaflet in a safe place so that the patient can read it again.
The different parts of the nasal spray: Protective cap: Keeps the nozzle clean and protects the jet. Always replace the protective cap after the patient ha used the nasal spray.
Jet: The tiny hole from which the solution sprays out.
Nozzle: The part to insert into the nostril.
Pump: The part the patient presses down to operate the spray.
Counter: The dose counter window on a new nasal spray show. The display will change as the patient uses the pump.
Dip tube: The tube inside the spray bottle that draws up the solution when the patient presses the pump.
Bottle: Contains enough solution for at least 14 doses.
Preparing a new nasal spray bottle for use: Never shake the nasal spray bottle as this could cause air bubbles, which may affect the dose.
First, remove the protective cap.
Hold the nasal spray upright in 1 or 2 hands and press down firmly on the pump 3 times.
This primes the new spray by clearing air out of the dip tube. This is only done once, when starting a new spray.
It is normal for a little solution to spray out.
As the pump is pressed, watch the changes in the dose counter window.
When green is shown in the dose counter window, the new nasal spray is ready to use.
Using the Nasal Spray: With the protective cap removed, bend the head of patient forward slightly and insert the nozzle into one of the nostrils. Try to hold the nasal spray upright.
Press the pump firmly, once only.
Remove the nasal spray from the nose and breathe in deeply through the nostril to help keep the solution in the nose.
If the physician has instructed to take 2 puffs at a time, repeat the procedure in the other nostril.
After use, clean the nozzle with a dry tissue and replace the protective cap.
Checking the Counter: Every time the nasal spray is used, the number in the dose counter window will change. The number displayed tells how many puffs are already taken. The nasal spray is guaranteed to deliver 14 metered doses. An additional 2 doses may be obtained.
When the dose counter window shows a red "16", 16 puffs have been used and the nasal spray is finished. A little liquid may be left in the nasal spray bottle, but this is normal.
Note when using nasal spray: If the spray mechanism should become blocked, this may be resolved by pressing down firmly on the pump; do not attempt to unblock it using a sharp pointed object as this may cause damage. If the nasal spray is not working properly, return it to the pharmacist. Never try to fix the nasal spray or to take it apart, as this may affect the dose.
Always follow the physician's instructions regarding dosage carefully.
Miacalcic Nasal Spray should be stored at 2-8°C. Do not freeze.
Once opened, it must be kept at room temperature (not above 25°C) and used within a maximum of 4 weeks.
Keep the bottle upright at all times to reduce the risk of air bubbles entering the dip tube.
H05BA01 - calcitonin (salmon synthetic) ; Belongs to the class of anti-parathyroid hormones, calcitonin preparations. Used in the management of calcium homeostasis.
Nasal spray 200 IU x 14 metered doses x 1's.