patients for whom other therapies are contraindicated or for patients who are intolerant or unwilling to use other therapies). 1.2 important limitations of use due to the possible association between malignancy and calcitonin salmon use, the need for continued therapy should be re-evaluated on a periodic basis [see warnings and precautions (5.4)] . calcitonin salmon (synthetic origin) nasal spray has not been shown to increase spinal bone mineral density in early postmenopausal women.

ave also been reported, including reports of death attributed to anaphylaxis. the usual provisions should be made for emergency treatment if such a reaction occurs. hypersensitivity reactions should be differentiated from generalized flushing and hypotension [see contraindications (4)] . for patients with suspected hypersensitivity to calcitonin salmon, skin testing should be considered prior to treatment utilizing a dilute, sterile solution of a calcitonin salmon injectable product. healthcare providers may wish to refer patients who require skin testing to an allergist. a detailed skin testing protocol is available from the customer service department of apotex corp. (1-800-706-5575). 5.2 hypocalcemia hypocalcemia associated with tetany (i.e., muscle cramps, twitching) and seizure activity has been reported with calcitonin therapy. hypocalcemia must be corrected before initiating therapy with calcitonin salmon nasal spray. other disorders affecting mineral metabolism (such as vitamin d deficiency) should also be effectively treated. in patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with calcitonin salmon nasal spray. use of calcitonin salmon nasal spray is recommended in conjunction with an adequate intake of calcium and vitamin d [see dosage and administration (2.3)] . 5.3 nasal adverse reactions adverse reactions related to the nose including rhinitis and epistaxis have been reported. development of mucosal alterations may occur. therefore, periodic nasal examinations with visualization of the nasal mucosa, turbinates, septum and mucosal blood vessels are recommended prior to start of treatment with calcitonin salmon nasal spray, periodically during the course of therapy, and at any time nasal symptoms occur. calcitonin salmon nasal spray should be discontinued if severe ulceration of the nasal mucosa occurs, as indicated by ulcers greater than 1.5 mm in diameter or penetrating below the mucosa, or those associated with heavy bleeding. although smaller ulcers often heal without withdrawal of calcitonin salmon nasal spray, medication should be discontinued temporarily until healing occurs [see adverse reactions (6.1)] . 5.4 malignancy in a meta-analysis of 21 randomized, controlled clinical trials with calcitonin salmon (nasal spray or investigational oral formulations), the overall incidence of malignancies reported was higher among calcitonin salmon-treated patients (4.1%) compared with placebo-treated patients (2.9%). this suggests an increased risk of malignancies in calcitonin salmon-treated patients compared to placebo-treated patients. the benefits for the individual patient should be carefully considered against possible risks [see adverse reactions (6.1)] . 5.5 antibody formation circulating antibodies to calcitonin salmon have been reported with calcitonin salmon nasal spray. the possibility of antibody formation should be considered in any patient with an initial response to calcitonin salmon nasal spray who later stops responding to treatment [see adverse reactions (6.3)] . 5.6 urine sediment abnormalities coarse granular casts and casts containing renal tubular epithelial cells were reported in young adult volunteers at bed rest who were given injectable calcitonin salmon to study the effect of immobilization on osteoporosis. there was no other evidence of renal abnormality and the urine sediment normalized after calcitonin salmon was stopped. periodic examinations of urine sediment should be considered. urine sediment abnormalities have not been reported in ambulatory volunteers treated with calcitonin salmon nasal spray.

rst be carefully placed into the nostril while the patient’s head is in the upright position, then the pump should be firmly depressed toward the bottle. the pump should not be primed before each daily dose. 2.3 recommendations for calcium and vitamin d supplementation patients who use calcitonin salmon nasal spray should receive adequate calcium (at least 1000 mg elemental calcium per day) and vitamin d (at least 400 international units per day).

menopausal osteoporosis was assessed in 5 randomized, double-blind, placebo controlled trials that enrolled postmenopausal women, aged 45 to 75 years. the duration of the trials ranged from 1 to 2 years. the incidence of adverse reactions reported in studies involving postmenopausal osteoporotic patients chronically exposed to calcitonin salmon nasal spray (n=341) and to placebo nasal spray (n=131), and reported in greater than 3% of calcitonin salmon nasal spray treated patients are presented in the following table. other than flushing, nausea, possible allergic reactions, and possible local irritative effects in the respiratory tract, a relationship to calcitonin salmon nasal spray has not been established. table 1: adverse reactions occurring in at least 3% of postmenopausal patients treated with calcitonin salmon nasal spray †symptom of nose includes: nasal crusts, dryness, redness or erythema, nasal sores, irritation, itching, thick feeling, soreness, pallor, infection, stenosis, runny/blocked, small wound, bleeding wound, tenderness, uncomfortable feeling and sore across bridge of nose. calcitonin salmon nasal spray placebo nasal spray adverse reaction n=341 % of patients n=131 % of patients rhinitis 12 7 symptom of nose† 11 16 back pain 5 2 arthralgia 4 5 epistaxis 4 5 headache 3 5 nasal adverse reactions in all postmenopausal patients treated with calcitonin salmon nasal spray, the most commonly reported nasal adverse reactions included rhinitis (12%), epistaxis (4%), and sinusitis (2%). smoking did not have a contributory effect on the occurrence of nasal adverse reactions. adverse reactions reported in 1% to 3% of patients treated with calcitonin salmon nasal spray include: influenza-like symptoms, erythematous rash, arthrosis, myalgia, sinusitis, upper respiratory tract infection, bronchospasm, abdominal pain, nausea, dizziness, paresthesia, abnormal lacrimation, conjunctivitis, lymphadenopathy, infection, and depression. malignancy a meta-analysis of 21 randomized, controlled clinical trials with calcitonin salmon (nasal spray or investigational oral formulations) was conducted to assess the risk of malignancies in calcitonin salmon-treated patients compared to placebo-treated patients. the trials in the meta-analysis ranged in duration from 6 months to 5 years and included a total of 10883 patients (6151 treated with calcitonin salmon and 4732 treated with placebo). the overall incidence of malignancies reported in these 21 trials was higher among calcitonin salmon-treated patients (254/6151 or 4.1%) compared with placebo-treated patients (137/4732 or 2.9%). findings were similar when analyses were restricted to the 18 nasal spray only trials [calcitonin salmon 122/2712 (4.5%); placebo 30/1309 (2.3%)]. the meta-analysis results suggest an increased risk of overall malignancies in calcitonin salmon-treated patients compared to placebo-treated patients when all 21 trials are included and when the analysis is restricted to the 18 nasal spray only trials (see table 2). it is not possible to exclude an increased risk when calcitonin salmon is administered by the subcutaneous, intramuscular, or intravenous route because these routes of administration were not investigated in the meta-analysis. the increased malignancy risk seen with the meta-analysis was heavily influenced by a single large 5-year trial, which had an observed risk difference of 3.4% [95% ci (0.4%, 6.5%)]. imbalances in risks were still observed when analyses excluded basal cell carcinoma (see table 2); the data were not sufficient for further analyses by type of malignancy. a mechanism for these observations has not been identified. although a definitive causal relationship between calcitonin salmon use and malignancies cannot be established from this meta-analysis, the benefits for the individual patient should be carefully evaluated against all possible risks [see warnings and precautions (5.4)] . table 2: risk difference for malignancies in calcitonin salmon-treated patients compared with placebo-treated patients 1 the overall adjusted risk difference is the difference between the percentage of patients who had any malignancy (or malignancy excluding basal cell carcinoma) in calcitonin salmon and placebo treatment groups, using the mantel-haenszel (mh) fixed-effect method. a risk difference of 0 is suggestive of no difference in malignancy risks between the treatment groups. 2 the corresponding 95% confidence interval for the overall adjusted risk difference also based on mh fixed-effect method. patients malignancies risk difference 1 (%) 95% confidence interval 2 (%) all (nasal spray + oral) all 1.0 (0.3, 1.6) all (nasal spray + oral) excluding basal cell carcinoma 0.5 (-0.1, 1.2) all (nasal spray only) all 1.4 (0.3, 2.6) all (nasal spray only) excluding basal cell carcinoma 0.8 (-0.2, 1.8) 6.2 postmarketing experience because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. the following adverse reactions have been reported during post-approval use of calcitonin salmon nasal spray. allergic / hypersensitivity reactions serious allergic reactions have been reported in patients receiving calcitonin salmon nasal spray, including anaphylaxis and anaphylactic shock. hypocalcemia hypocalcemia with paresthesia has been reported. body as a whole facial or peripheral edema cardiovascular hypertension, vasodilatation, syncope, chest pain nervous system dizziness, seizure, visual or hearing impairment, tinnitus respiratory/special senses cough, bronchospasm, dyspnea, loss of taste/smell skin rash/dermatitis, pruritus, alopecia, increased sweating gastrointestinal diarrhea nervous system disorders tremor 6.3 immunogenicity consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of calcitonin salmon nasal spray may trigger the development of anti-calcitonin antibodies. in a two-year calcitonin salmon nasal spray clinical study that evaluated immunogenicity, a measurable antibody titer was found in 69% of patients treated with calcitonin salmon nasal spray and 3% of placebo-treated patients. antibody formation may be associated with a loss of response to treatment [see warnings and precautions (5.5)] . the incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. additionally, the observed incidence of a positive antibody test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. for these reasons, comparison of antibodies to calcitonin salmon nasal spray with the incidence of antibodies to other calcitonin-containing products may be misleading.

e intranasal dose recommended for human use based on body surface area. no embryo/fetal toxicities related to calcitonin salmon nasal spray were reported from maternal subcutaneous daily doses in rats up to 80 international units/kg/day from gestation day 6 to 15. 8.2 lactation risk summary calcitonin salmon nasal spray is not indicated for use in females of reproductive potential. there is no information on the presence of calcitonin-salmon in human milk, the effects on the breastfed child, or the effects on milk production. calcitonin has been shown to inhibit lactation in rats. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use in a multi-centered, double-blind, randomized clinical study of calcitonin salmon nasal spray, 279 patients were less than 65 years old, while 467 patients were 65 to 74 years old and 196 patients were 75 years old and older. compared to subjects less than 65 years old, the incidence of nasal adverse reactions (rhinitis, irritation, erythema, and excoriation) was higher in patients over the age of 65, particularly among those over the age of 75. other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

e reported from maternal subcutaneous daily doses in rats up to 80 international units/kg/day from gestation day 6 to 15.

ferent. bone single injections of calcitonin salmon caused a marked transient inhibition of the ongoing bone resorptive process. with prolonged use, there is a persistent, smaller decrease in the rate of bone resorption. histologically, this is associated with a decreased number of osteoclasts and an apparent decrease in their resorptive activity. in healthy adults, who have a relatively low rate of bone resorption, the administration of exogenous calcitonin salmon results in decreases in serum calcium within the limits of the normal range. in healthy children and in patients whose bone resorption is more rapid, decreases in serum calcium are more pronounced in response to calcitonin salmon. kidney studies with injectable calcitonin salmon show increases in the excretion of filtered phosphate, calcium, and sodium by decreasing their tubular reabsorption. comparable studies have not been conducted with calcitonin salmon nasal spray. gastrointestinal tract some evidence from studies with injectable preparations suggests that calcitonin salmon may have effects on the gastrointestinal tract. short-term administration of injectable calcitonin salmon results in marked transient decreases in the volume and acidity of gastric juice and in the volume and the trypsin and amylase content of pancreatic juice. whether these effects continue to be elicited after each injection of calcitonin salmon during chronic therapy has not been investigated. these studies have not been conducted with calcitonin salmon nasal spray. calcium homeostasis in two clinical studies designed to evaluate the pharmacodynamic response to calcitonin salmon nasal spray, administration of calcitonin salmon 100 to 1600 international units to healthy volunteers resulted in rapid and sustained decreases within the normal range for both total serum calcium and serum ionized calcium. single doses of calcitonin salmon greater than 400 international units did not produce any further biological response to the drug. 12.3 pharmacokinetics the bioavailability of calcitonin salmon nasal spray relative to intramuscular administration in healthy volunteers is between 3% and 5%. calcitonin salmon nasal spray is absorbed rapidly by the nasal mucosa with a mean t max of about 13 minutes. the terminal half-life of calcitonin salmon has been calculated to be around 18 minutes and no evidence of accumulation was observed with multiple dosing.

etween 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 2 times the maximum recommended intranasal dose in humans (200 international units/day) based on body surface area conversion between rats and humans and a 20-fold conversion factor to account for decreased clinical exposure via the intranasal route. 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 390 times the maximum recommended intranasal dose in humans (200 international units) based on scaling for body surface area and a 20-fold conversion factor to account for low clinical exposure via the intranasal route. 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.

ng 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 2 times the maximum recommended intranasal dose in humans (200 international units/day) based on body surface area conversion between rats and humans and a 20-fold conversion factor to account for decreased clinical exposure via the intranasal route. 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 390 times the maximum recommended intranasal dose in humans (200 international units) based on scaling for body surface area and a 20-fold conversion factor to account for low clinical exposure via the intranasal route. 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.

mineral density in women greater than 5 years postmenopause with low bone mass itt: intent to treat iu: international units ns: nasal spray †p-values by parametric testing (2-tailed 2-sample t-test) lumbar spine bone mineral density, mean change from baseline (in %) at month 24 study 1 (with calcium supplement) n (itt) = 100 study 2 (no calcium supplement) n (itt) = 39 calcitonin salmon 200 iu ns daily +1.56 +1.02 placebo +0.20 -1.85 treatment difference +1.36 +2.87 p-value† < 0.05 < 0.005 no effects of calcitonin salmon nasal spray on cortical bone of the forearm or hip were demonstrated. in clinical studies of postmenopausal osteoporosis, bone biopsy and radial bone mass assessments at baseline and after 26 months of daily injectable calcitonin salmon indicate that calcitonin therapy results in the formation of normal bone.

f a serious allergic reaction. advise patients how to correctly store unopened and opened product [see how supplied/storage and handling (16)] . advise patients that the bottle should be discarded after 14 doses (2 ml fill) or 30 doses (3.7 ml fill), because after 14 or 30 doses, each spray may not deliver the correct amount of medication even if the bottle is not completely empty. apotex inc. calcitonin salmon (synthetic origin) nasal spray manufactured by manufactured for apotex inc. apotex corp. toronto, ontario weston, fl canada m9l 1t9 33326 revised: november 2017

known if calcitonin salmon (synthetic origin) nasal spray is safe and effective in children under 18 years of age. who should not use calcitonin salmon (synthetic origin) nasal spray? do not use calcitonin salmon (synthetic origin) nasal spray if you: are allergic to calcitonin salmon or any of the ingredients in calcitonin salmon (synthetic origin) nasal spray. see the end of this leaflet for a complete list of ingredients in calcitonin salmon (synthetic origin) nasal spray. what should i tell my healthcare provider before using calcitonin salmon (synthetic origin) nasal spray? before you use calcitonin salmon (synthetic origin) nasal spray, tell your healthcare provider if you: have any other medical conditions have low calcium levels in your blood are pregnant or plan to become pregnant. it is not known if calcitonin salmon (synthetic origin) nasal spray can harm your unborn baby. are breastfeeding or plan to breastfeed. it is not known if calcitonin salmon passes into your breast milk. you and your healthcare provider should decide if you will use calcitonin salmon (synthetic origin) nasal spray or breastfeed. tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. especially tell your healthcare provider if you take: lithium. your healthcare provider may need to change your dose of lithium while you use calcitonin salmon (synthetic origin) nasal spray. know the medicines you take. keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. how should i use calcitonin salmon (synthetic origin) nasal spray? for detailed instructions, see the instructions for use at the end of this patient information leaflet. use calcitonin salmon (synthetic origin) nasal spray exactly as your healthcare provider tells you to use it. do not use calcitonin salmon (synthetic origin) nasal spray until your healthcare provider shows you and you understand how to use it correctly. use 1 spray of calcitonin salmon (synthetic origin) nasal spray, 1 time each day, in 1 nostril (inside your nose). start with 1 spray in your left nostril on your first day, followed by 1 spray in your right nostril on the second day. continue to switch nostrils for your dose each day. your healthcare provider should check your nose before you start using calcitonin salmon (synthetic origin) nasal spray and often while you are using it. tell your healthcare provider if you start to have discomfort (irritation) in your nose that bothers you while you use calcitonin salmon (synthetic origin) nasal spray. your health care provider should prescribe calcium and vitamin d to help prevent low calcium levels in your blood while you use calcitonin salmon (synthetic origin) nasal spray. take your calcium and vitamin d as your healthcare provider tells you to. there are 14 doses (2 ml fill) or 30 doses (3.7 ml fill) (sprays) of calcitonin salmon (synthetic origin) nasal spray in each bottle. after either 14 doses (2 ml fill) or 30 doses (3.7 ml fill), each spray may not give you the right amount of medicine, even if the bottle is not completely empty. keep track of the number of doses of medicine used from your bottle. if you use too much calcitonin salmon (synthetic origin) nasal spray, call your healthcare provider or go to the nearest hospital emergency room right away. what are the possible side effects of calcitonin salmon (synthetic origin) nasal spray? calcitonin salmon (synthetic origin) nasal spray may cause serious side effects, including: allergic reactions some people have had an allergic reaction when using calcitonin salmon nasal spray. some reactions may be serious and can be life threatening. call your healthcare provider or go to the nearest hospital emergency room right away if you have any of these symptoms of an allergic reaction. trouble breathing swelling of your face, throat or tongue fast heartbeat chest pain feel dizzy or faint if you might be allergic to calcitonin salmon, your healthcare provider should do a skin test before you use calcitonin salmon (synthetic origin) nasal spray. low calcium levels in your blood (hypocalcemia) calcitonin salmon (synthetic origin) nasal spray may lower the calcium levels in your blood. if you have low blood calcium before you start using calcitonin salmon (synthetic origin) nasal spray, it may get worse during treatment. your low blood calcium must be treated before you use calcitonin salmon (synthetic origin) nasal spray. most people with low blood calcium levels do not have symptoms, but some people may have symptoms. call your healthcare provider right away if you have any of these symptoms of low blood calcium: numbness or tingling in your fingers, toes, or around your mouth your healthcare provider should: do blood tests while you use calcitonin salmon (synthetic origin) nasal spray prescribe calcium and vitamin d to help prevent low calcium levels in your blood while you use calcitonin salmon (synthetic origin) nasal spray. take your calcium and vitamin d as your healthcare provider tells you to. nose irritation irritation of your nose can happen while you are using calcitonin salmon (synthetic origin) nasal spray, especially if you are over 65 years of age. call your healthcare provider right way if you have any of these symptoms of nose irritation: crusting dryness redness or swelling nose sores (ulcers) nose bleeds your healthcare provider may stop your treatment with calcitonin salmon (synthetic origin) nasal spray until your nose irritation symptoms go away. risk of cancer people who use calcitonin salmon, the medicine in calcitonin salmon (synthetic origin) nasal spray, may have an increased risk of cancer. increase of certain cells (sediment) in your urine your healthcare provider should test your urine often while you are using calcitonin salmon (synthetic origin) nasal spray. the most common side effects of calcitonin salmon (synthetic origin) nasal spray include: back pain muscle aches headache runny nose these are not all the possible side effects of calcitonin salmon (synthetic origin) nasal spray. for more information, ask your healthcare provider or pharmacist. tell your healthcare provider right away if you have any side effect that bothers you or does not go away. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. how do i store calcitonin salmon (synthetic origin) nasal spray? store open bottles of calcitonin salmon (synthetic origin) nasal spray at room temperature between 20°c to 25°c (68°f to 77°f) for 30 days (2 ml fill) or 35 days (3.7 ml fill). store unopened bottles of calcitonin salmon (synthetic origin) nasal spray in the refrigerator between 2°c to 8°c (36°f to 46°f). do not freeze. store calcitonin salmon (synthetic origin) nasal spray bottles in an upright position. safely throw away calcitonin salmon (synthetic origin) nasal spray in the trash after you have used 14 doses (2 ml fill) or 30 doses (3.7 ml fill) (sprays). keep calcitonin salmon (synthetic origin) nasal spray and all other medicines out of the reach of children. general information about the safe and effective use of calcitonin salmon (synthetic origin) nasal spray. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use calcitonin salmon (synthetic origin) nasal spray for a condition for which it was not prescribed. do not give calcitonin salmon (synthetic origin) nasal spray to other people, even if they have the same symptoms you have. it may harm them. this patient information summarizes the most important information about calcitonin salmon (synthetic origin) nasal spray. if you would like more information, talk with your healthcare provider. you can ask your pharmacist or healthcare provider for information about calcitonin salmon (synthetic origin) nasal spray that is written for health professionals. for more information, call 1-800-706-5575. what are the ingredients in calcitonin salmon (synthetic origin) nasal spray? active ingredients: calcitonin salmon inactive ingredients: benzalkonium chloride, hydrochloric acid, purified water and sodium chloride.