Calcitonin

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

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

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. Therefore, breast-feeding is not recommended during treatment.

Carcinogenicity

The incidence of pituitary adenomas was increased in rats after one and two years of subcutaneous exposure to synthetic calcitonin salmon. The significance of this finding to humans is unknown because pituitary adenomas are very common in rats as they age, the pituitary adenomas did not transform into metastatic tumors, there were no other clear treatment-related neoplasms, and synthetic calcitonin salmon related neoplasms were not observed in mice after two years of dosing.

Rat findings

The only clear neoplastic finding in rats dosed subcutaneously with calcitonin salmon was an increase in the incidence of pituitary adenomas in male Fisher 344 rats and female Sprague Dawley rats after one year of dosing and male Sprague Dawley rats dosed for one and two years. In female Sprague Dawley rats, the incidence of pituitary adenomas after two years was high in all treatment groups (between 80% and 92% including the control groups) such that a treatment-related effect could not be distinguished from natural background incidence. The lowest dose in male Sprague Dawley rats that developed an increased incidence of pituitary adenomas after two years of dosing (1.7 International Units/kg/day) is approximately 1/6th of the maximum recommended subcutaneous dose in humans (100 International Units/day) based on body surface area conversion between rats and humans. The findings suggest that calcitonin salmon reduced the latency period for development of non-functioning pituitary adenomas.

Mouse findings

No carcinogenicity potential was evident in male or female mice dosed subcutaneously for two years with synthetic calcitonin salmon at doses up to 800 International Units/kg/day. The 800 International Units/kg/day dose is approximately 39 times the maximum recommended subcutaneous dose in humans (100 International Units/day) based on body surface area conversion between mice and humans.

Mutagenesis

Synthetic calcitonin salmon tested negative for mutagenicity using Salmonella typhimurium (5 strains) and Escherichia coli (2 strains), with and without rat liver metabolic activation, and was not clastogenic in a chromosome aberration test in Chinese Hamster V79 cells. There was no evidence that calcitonin salmon was clastogenic in the in vivo mouse micronucleus test.

Fertility

Effects of calcitonin salmon on fertility have not been assessed in animals.

No studies exist on the effects of Calcitonin on the ability to drive and use machines. Calcitonin may cause fatigue, dizziness and visual disturbances 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 more frequent after i.v. than after i.m. or s.c. administration.

Adverse drug reactions from multiple sources including clinical trials and post-marketing experience are 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.

Adverse reactions have been ranked under headings of frequency using the following convention: 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 (cannot be estimated from the available data).

The frequencies of the above listed undesirable effects are partly based on results from clinical trials with nasal spray.

¹ Development of neutralising antibodies to calcitonin. 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.

² Nausea 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 the injection is done in the evening and after meals.

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

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