Miacalcic® 400 IU/2ml Solution for Injection and Infusion.

Multidose vials containing calcitonin 400IU/ml

For the full list of excipients, see section 6.1.

Solution for injection and infusion.

Maicalcic 400 IU/2ml is a clear colourless aqueous solution.

Calcitonin is indicated for:

• Prevention of acute bone loss due to sudden immobilisation such as in patients with recent osteoporotic fractures

• Paget's disease

• Hypercalcaemia of malignancy

The solution provided in the multidose vial can be used for subcutaneous or intramuscular injection or for continuous i.v. infusion , but is not suitable for i.v. bolus injection as it contains phenol (5mg/mL) as a preservative.

Salmon calcitonin may be administered at bedtime to reduce the incidence of nausea or vomiting which may occur, especially at the initiation of therapy.

Prevention of acute bone loss:

The recommended dosage is 100 I.U. daily or 50 I.U. twice daily for 2 to 4 weeks, administered subcutaneously or intramuscularly. The dose may be reduced to 50 IU. daily at the start of remobilisation. The treatment should be maintained until patients are fully mobilised.

Paget's Disease:

The recommended dosage is 100 I.U. per day administered subcutaneously or intramuscularly, however a minimum dosage regimen of 50 I.U. three times a week has achieved clinical and biochemical improvement. Dosage is to be adjusted to the individual patient's needs. The duration of treatment depends on the indication for treatment and the patient's response. The effect of calcitonin may be monitored by measurement of suitable markers of bone remodelling, such as serum alkaline phosphatase or urinary hydroxyproline or deoxypyridinoline. The dose may be reduced after the condition of the patient has improved.

Hypercalcaemia of malignancy:

The recommended starting dose is 100 I.U. every 6 to 8 hours by subcutaneous or intramuscular injection. In addition, salmon calcitonin could be administered by intravenous injection after previous rehydration.

If the response is not satisfactory after one or two days, the dose may be increased to a maximum of 400 I.U. every 6 to 8 hours. In severe or emergency cases, intravenous infusion with up to 10 I.U./kg body weight in 500 ml 0.9% w/v sodium chloride solution may be administered over a period of at least 6 hours.

As salmon calcitonin is a peptide, adsorption onto the plastic of the infusion set may occur. This has the potential to reduce the total dose delivered to the patient. Frequent monitoring of the clinical and laboratory response including the measurement of serum calcium is recommended especially in the early phase of treatment. The dosing of Miacalcic should be individualized to the patient's specific requirements

Use in elderly, hepatic and renal impairment patients

Experience with the use of calcitonin in the elderly has shown no evidence of reduced tolerability or altered dosage requirements. The same applies to patients with altered hepatic function. The metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevance of this finding is not known. (see section 5.2).

Use in children

There is insufficient evidence to support the use of salmon calcitonin in conditions associated with paediatric osteoporosis. Use of salmon calcitonin in children 0 to 18 years is therefore not recommended.

Hypersensitivity to active substance or to any of the excipients listed in section 6.1.

Calcitonin is also contraindicated in patients with hypocalcaemia.

Because calcitonin is a peptide, the possibility of systemic allergic reactions exists and allergic-type reactions including isolated cases of anaphylactic shock have been reported in patients receiving calcitonin. Such reactions should be differentiated from generalised or local flushing, which are common non-allergic effects of calcitonin (see 4.8). Skin testing should be conducted in patients with suspected sensitivity to calcitonin prior to their treatment with calcitonin.

Serum calcium levels may be transiently decreased to below normal levels following administration of calcitonin, notably upon initiation of therapy in patients with abnormally high rates of bone turnover. This effect is diminished as osteoclastic activity is reduced. However, care should be exercised in patients receiving concurrent treatment with cardiac glycosides or calcium channel blocking agents. Dosages of these drugs may require adjustment in view of the fact that their effects may be modified by changes in cellular electrolyte concentrations.

The use of calcitonin in combination with bisphosphonates may result in an additive calcium-lowering effect.

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

Calcitonin has not been studied in pregnant women. Calcitonin should be used during pregnancy only if treatment is considered absolutely essential by the physician.

Breast-feeding

It is not known if the substance is excreted in human milk. In animals, salmon calcitonin has been shown to decrease lactation and to be excreted in milk (see 5.3). Therefore, breast-feeding is not recommended during treatment.

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 section 4.8 Undesirable effects) which may impair the patient's reaction. Patients must therefore be warned that these effects may occur, in which case they should not drive or use machines.

The most frequently observed undesirable effects are nausea, vomiting and flushing. They are dose dependent and are more frequent after i.v. than after i.m. or s.c administration.

Adverse reactions have been ranked under headings of frequency using the following convention

Very common (1/10); common (1/100, <1/10); uncommon (1/1000, <1/100); rare (1/10,000, <1/1,000); very rare (<1/10,000) ,not known (cannot be estimated from the available data).

The frequencies of the above listed undesirable effects are partly based on results from clinical trials with Miacalcic Nasal Spray

¹ Neutralising antibodies to calcitonin rarely develop. The development of these antibodies is not usually related to loss of clinical efficacy, although their presence in a small percentage of patients following long-term therapy with calcitonin may result in a reduced response to the product. The presence of antibodies appears to bear no relationship to allergic reactions, which are rare. Calcitonin receptor down-regulation may also result in a reduced clinical response in a small percentage of patients following long term therapy.

²Nausea with or without vomiting is noted in approximately 10% of patients treated with calcitonin. The effect is more evident on initiation of therapy and tends to decrease or disappear with continued administration or a reduction in dose. An antiemetic may be administered, if required. Nausea/vomiting are less frequent when injection is done in the evening and after meals.

³In case of patients with high bone remodelling (Paget's disease and young patients) a transient decrease of calcaemia may occur between the 4^th and the 6^th hour after administration, usually asymptomatic.

⁴Flushing (facial or upper body)is not an allergic reaction but is due to pharmacological effect, and is usually observed 10 to 20 minutes after administration.

Nausea, vomiting, flushing and dizziness are known to be dose dependent when calcitonin is administered parenterally. Single doses (up to 10,000 I.U.) of injectable salmon calcitonin have been administered without adverse reactions, other than nausea and vomiting, and exacerbation of pharmacological effects.

Should symptoms of overdose appear, treatment should be symptomatic.

Pharmacotherapeutic group:antiparathyroid hormone, ATC code: H05BA01 (calcitonin, salmon).

The pharmacological properties of the synthetic and recombinant peptides have been demonstrated to be qualitatively and quantitatively equivalent.

Calcitonin is a calciotropic hormone, which inhibits bone resorption by a direct action on osteoclasts. By inhibiting osteoclast activity via its specific receptors, salmon calcitonin decreases bone resorption. In pharmacological studies, calcitonin has been shown to have analgesic activity in animal models.

Calcitonin markedly reduces bone turnover in conditions with an increased rate of bone resorption such as Paget's disease and acute bone loss due to sudden immobilisation. The absence of mineralisation defect with calcitonin has been demonstrated by bone histomorphometric studies both in man and in animals.

Decreases in bone resorption as judged by a reduction in urinary hydroxylproline and deoxypyridinoline are observed following calcitonin treatment in both normal volunteers and patients with bone-related disorders, including Paget's disease and osteoporosis.

The calcium-lowering effect of calcitonin is caused both by a decrease in the efflux of calcium from the bone to the ECF and inhibition of renal tubular reabsorption of calcium.

General characteristics of the active substance

Salmon calcitonin is rapidly absorbed and eliminated. Peak plasma concentrations are attained within the first hour of administration. After subcutaneous administration, peak plasma levels are reached in about 23 minutes.

Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidney following parenteral administration. The metabolites lack the specific biological activity of calcitonin. Bioavailability following subcutaneous and intramuscular injection in humans is high and similar for the two routes of administration (71% and 66%, respectively).

Calcitonin has a short absorption half –life of 10-15 minutes. The elimination half-life is about 1 hour for intramuscular administration and 1 to 1.5 hours for subcutaneous administration. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically inactive fragments of the molecule. Therefore, the metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevance of this finding is not known.

Plasma protein binding is 30 to 40%.

Characteristics in patients

There is a relationship between the subcutaneous dose of calcitonin and peak plasma concentrations. Following parenteral administration of 100 I.U. calcitonin, peak plasma concentration lies between about 200 and 400 pg/ml. Higher blood levels may be associated with increased incidence of nausea and vomiting.

Conventional long term toxicity, reproduction, mutagenicity and carcinogenicity studies have been performed in laboratory animals.

Salmon calcitonin is devoid of embryotoxic, teratogenic and mutagenic potential.

An increased incidence of pituitary adenomas has been reported in rats given synthetic salmon calcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance. Salmon calcitonin does not cross the placental barrier.

In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin is secreted into the milk.

Multidose vials: glacial acetic acid, sodium acetate trihydrate, sodium chloride, water for injection, phenol.

None

Multidose vials - 48 months (1 month after initial use).

Store in a refrigerator (2-8°C). Do not allow to freeze.

Allow to reach room temperature before subcutaneous or intramuscular use.

Multidose vials - Discard unused portion of contents one month after initial use. Once started, the MDV can be stored at room temperature.

Uncoloured type I glass vial, with latex free rubber stopper.

Allow to reach room temperature before intramuscular or subcutaneous use. Solutions for infusions should be prepared immediately before use and glass or hard plastic containers should not be used.

Novartis Pharmaceuticals UK Limited

Trading as: Sandoz Pharmaceuticals

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

PL 00101/0203

23 July 1990 / 24 October 2002

29 December 2011

POM