The active substance is synthetic salmon calcitonin (INN name Calcitonin). One millilitre contains 100 IU of synthetic salmon calcitonin. One International Unit (= IU) corresponds to about 0.2 micrograms of synthetic salmon calcitonin. For excipients see List of excipients.
Miacalcic is available as a solution for injection or infusion in ampoules (1 mL) containing 100 IU/mL.
Miacalcic solution for injection or infusion is indicated for:
Acute bone pain associated with hip arthroplasty osteolysis and osteoporotic vertebral compression fracture
Paget's disease of bone (osteitis deformans), only in patients with the following conditions and who do not respond to alternative treatments or for whom such treatments are not suitable:
Bone pain
Neurological complications
Increased bone turnover reflected in elevated serum alkaline phophastase and urinary hydroxyproline excretion
Progressive extension of bone lesions
Incomplete or repeated fractures
Hypercalcaemia and hypercalcaemic crisis due to
tumoural osteolysis secondary to breast, lung or kidney carcinoma, myeloma and other malignancies, hyperparathyroidism, immobilisation or vitamin D intoxication, for both the acute treatment of emergencies and the prolonged treatment of chronic hypercalcaemia, until specific therapy of the underlying condition proves effective.
Neurodystrophic disorders (synonymous with algodystrophy, Sudeck's disease or complex regional pain syndrome), in conjunction with physiotheraphy
Caused by various aetiological and predisposing factors such as post-traumatic painful osteoporosis, reflex dystrophy, shoulder-arm syndrome, causalgia, drug-induced neurotrophic disorders. In patients who do not respond to alternative treatments or for whom such treatments are not suitable
Adjuvant therapy of acute pancreatitis
Patients should receive precise instruction in the self-administration of subcutaneous injections from the physician or the nurse. Due to the association between occurrence of malignancies and long-term calcitonin use (see Warnings and precautions), the treatment duration in all indications should be limited to the shortest period of time possible and using the lowest effective dose. It is recommended that use of Miacalcic be accompanied by an adequate intake of calcium and vitamin D to prevent progressive loss of bone mass.
The recommended dose is 100 to 200 IU daily by slow i.v. infusion in physiological saline, or by s.c. or i.m. injection in divided doses spread over the day, until a satisfactory response is achieved. Dosage should be adjusted to the individual patient's needs. It may take several days of treatment until the analgesic effect is fully developed. Treatment should normally be for up to four weeks.
In Paget's disease the recommended dose is 100 IU daily or every second day by s.c. or i.m. injection. The duration of treatment depends on the therapeutic indication and the patient's response. Dosage should be adjusted to the individual patient's needs. 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.
Emergency treatment of hypercalcaemic crisis:
Intravenous infusion is the most effective method of administration and should therefore be preferred in the treatment of emergencies or other severe conditions. The recommended dose is 5 to 10 IU per kg body weight in 500 mL physiological saline daily by i.v. infusion over at least six hours, or by slow i.v. injection in 2 to 4 divided doses spread over the day.
Treatment of hypercalcaemia:
Treatment should be limited to the shortest duration possible. The recommended dosage in treatment of hypercalcaemic states is 5 to 10 IU per kg body weight daily by s.c. or i.m. injection as a single dose or in two divided doses. Treatment should be adjusted to the patient's clinical and biochemical response. If the volume of Miacalcic to be injected exceeds 2 mL, i.m. administration is preferable and multiple sites of injection should be used.
Early diagnosis of neurodystrophic disorders is essential and treatment should start as soon as the diagnosis is confirmed. The recommended dosage is 100 IU daily by s.c. or i.m. injection for 2 to 4 weeks. An additional 100 IU may be given every second day for up to 6 weeks depending on clinical progress.
The recommended dosage of 300 IU by i.v. infusion in physiological saline over a 24 hours period for up to 6 consecutive days.
Treatment should be limited to the shortest duration possible. Antibodies to calcitonins may develop in patients under long-term therapy; clinical efficacy, is usually not affected, however. Escape phenomena, which occur in particular in pagetic patients receiving long-term therapy, may be due to saturation of the binding sites and are apparently not related to the development of antibodies. Following interruption of treatment, the therapeutic response to Miacalcic is restored.
There is limited experience with the use of parenteral Miacalcic in children, therefore no recommendations can be given for this patient group.
Extensive experience with the use of parenteral Miacalcic in the elderly has shown no evidence of reduced tolerance or altered dosage requirements. The same applies to patients with altered renal or hepatic function, although no formal studies have been carried out in this specific patient population.
Known hypersensitivity to synthetic salmon calcitonin or to any of the excipients (see Special warnings and precautions for use, Adverse effects and List of excipients).
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. 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 effects). These 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 intra-nasal formulations however it cannot be excluded that an increased risk also applies when calcitonin is administered long-term subcutaneously, intramuscularly or intravenously. The benefits for the individual patient should be carefully evaluated against possible risks (see Adverse effects). Miacalcic Ampoules contain less than 23 mg sodium per 1 mL, and can therefore be considered "sodium-free".
Concomitant use of calcitonin and lithium may lead to a reduction in plasma lithium concentrations. The dose of lithium may need to be adjusted.
Pregnancy:
Since no studies have been carried out in pregnant women, Miacalcic should not be administered to such patients. Animal studies have, however, shown that salmon calcitonin is devoid of embryotoxic and teratogenic potential. It appears that salmon calcitonin does not cross the placental barrier in animals.
Lactation:
Since no studies have been carried out in nursing mothers and it is not known whether salmon calcitonin is excreted in human milk, breast-feeding during treatment is not recommended.
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 effects), 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.
Nausea, vomiting, flushing and dizziness are dose-dependent and are more frequent after i.v. than after i.m. or s.c. administration. Polyuria and chills usually subside spontaneously and a temporary dose reduction is necessary in a few cases only. Adverse reactions (Table 1) are ranked under heading of frequency estimates, the most frequent first, using the following convention: very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1,000 and < 1/100); rare ( 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.
Table 1
Immune system disorders
Rare:Hypersensitivity. Very rare:Anaphylactic and anaphylactoid reactions, anaphylactic shock.
Nervous system disorders
Common:Dizziness, headache, dysgeusia. |
|---|
| Eye disorders Uncommon:Visual disturbance. |
| Vascular disorders Common:Flushing. Uncommon:Hypertension. |
| Gastrointestinal disorders Common:Nausea, diarrhoea, abdominal pain. Uncommon:Vomiting. |
| Skin and subcutaneous tissue disorders Rare:Rash generalised. |
| Musculoskeletal and connective tissue disorders Common:Arthralgia. Uncommon:Musculoskeletal pain. |
| Renal and urinary disorders Rare:Polyuria. |
| General disorders and administration site conditions Common:Fatigue. Uncommon:Influenza-like symptoms, oedema (facial, peripheral and generalised). Rare:Injection site reactions, pruritus. |
| Investigations Rare:Development of neutralising antibodies to calcitonin |
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 section Warnings and precautions).
Adverse drug reactions from spontaneous reports and literature cases (frequency not known)
The following reaction has been identified through post-marketing reporting and literature review. Because this adverse drug reaction has been reported voluntarily from a population of uncertain size, it is not possible to reliably estimate its frequency which is therefore categorized as not known.
Central and peripheral nervous system
: Tremor
Nausea, vomiting, flushing and dizziness are known to be dose-dependent when Miacalcic is administered parenterally. Nausea and vomiting have occurred following administration of Miacalcic as a parenteral overdose, but severe adverse reactions due to overdosage have so far not been reported. Treatment would be symptomatic.
Pharmacotherapeutic group: Regulator of calcium homeostasis (ATC code H05B A01). 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 significantly suppresses biochemical markers of bone turnover such as pyridinoline-crosslinks and skeletal isoenzymes of alkaline phosphatase. Calcitonin reduces gastric and exocrine pancreatic secretion. Owing to these properties, Miacalcic has been shown to be beneficial in the medical treatment of acute pancreatitis.
The absolute bioavailability of salmon calcitonin is about 70% after either intramuscular (i.m.) or subcutaneous (s.c.) injection. Peak plasma concentrations are attained within one hour. After subcutaneous administration, peak plasma levels are reached in about 23 minutes. The elimination half-life is about 1 hour for i.m. administration and 1 to 1.5 hours for s.c. administration. Salmon calcitonin and its metabolites are excreted up to 95% by the kidney, the fraction of parent drug being 2%. The apparent volume of distribution is 0.15-0.3 L/kg, and protein binding amounts to 30-40%.
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 tumours 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 about 760 times greater than that in humans following a dose of 50 IU, suggested that pituitary tumor induction is specific to the rat. In vivo nonclinical safety data do not support an association of salmon calcitonin treatment with malignancies and do not provide any evidence for tumor progression. Furthermore, there have been no reports of adverse events relating to pituitary tumours in patients. There is therefore enough evidence to conclude that pituitary tumour induction is a rat-specific event and that rat pituitary tumours have no relevance for the clinical use of Miacalcic.
Ampoules: Acetic acid, sodium acetate trihydrate, sodium chloride, water for injections.
None.
Ampoules: 5 years, if unopened.
Miacalcic Ampoules should be stored at temperatures of 2-8degC. Refrigerate do not freeze. Once opened, the ampoules should be used immediately and not stored, since they do not contain a preservative. Miacalcic Ampoules should be kept out of the reach and sight of children.
Colourless glass OPC (One-Point-Cut) ampoules (glass type I). Each ampoule contains 100IU/mL. Each pack of Miacalcic contains five ampoules.
Miacalcic Ampoules should be inspected visually. If the solution is not clear and colourless, or contains any particles, or if the ampoule is damaged, do not administer the solution. The ampoules are for single use only. Remaining contents should be discarded. Allow to reach room temperature before intramuscular or subcutaneous use.
Prescription Medicine
Novartis New Zealand Limited Private Bag 65904 Mairangi Bay Auckland 0754 Building G, 5 Orbit Drive Rosedale Auckland 0632 Telephone: 09 361 8100
29 April 2013 (Ref: BPI dated 16-July-2012)