CALCITONIN SALMON: 602 Adverse Event Reports & Safety Profile

Calcitonin is a polypeptide hormone secreted by the parafollicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish. Calcitonin salmon injection USP, synthetic is a synthetic polypeptide of 32 amino acids in the same linear sequence that is found in calcitonin of salmon origin. This is shown by the following graphic formula: Calcitonin salmon, USP is a white to off-white powder. It is soluble in water and 1% aqueous acetic acid. Its chemical name is L-cysteinyl-L-seryl-L-asparginyl-L-leucyl-L-seryl-L-threonyl-L-cysteinyl-L-valyl-L-leucyl-glycyl-L-lysyl-L-leucyl-L-seryl-L-glutaminyl-L-alpha-glutamyl-L-leucyl-L-histidyl-L-lysyl-L-leucyl-L-glutaminyl-Lthreonyl-L-tyrosyl-L-prolyl-L-arginyl-L-threonyl-L-asparginyl-L-threonyl-glycyl-L-seryl-glycyl-Lthreonyl-L-prolinamide (1->7)-disulfide and chemical structure is: Its molecular formula is C 145 H 240 N 44 O 48 S 2 and its molecular weight is 3432 Daltons. Calcitonin salmon injection, USP, synthetic, 400 USP Units/2 mL (200 USP Units/mL) is available as a sterile, clear, colorless solution filled in individual 2 mL multiple-dose clear glass vials for subcutaneous or intramuscular injection.

Each

1 mL contains: Active: Calcitonin salmon, USP …………………………...…….0.03333 mg (equivalent to 200 USP calcitonin salmon units) Inactives: Acetic acid, USP ............................................................... 2.25 mg Phenol, USP ...................................................................... 5.00 mg Sodium acetate trihydrate, USP………………….……...... 2.00 mg Sodium chloride, USP ....................................................... 7.50 mg Water for injection, USP, q.s. to ........................................ 1.00 mL The activity of calcitonin salmon injection, USP is stated in International Units based on bioassay in comparison with the International Reference Preparation of calcitonin salmon for Bioassay, distributed by the National Institute for Biological Standards and Control, Holly Hill, London. graphic 1

AND USAGE Calcitonin-salmon synthetic injection is a calcitonin, indicated for the following conditions:

• Treatment of symptomatic Paget’s disease of bone when alternative treatments are not suitable ( 1.1 )
• Treatment of hypercalcemia ( 1.2 )
• Treatment of postmenopausal osteoporosis when alternative treatments are not suitable. Fracture reduction efficacy has not been demonstrated ( 1.3 ) 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 ( 1.4 , 5.3 )

1.1 Treatment of Paget's Disease of Bone Calcitonin-salmon injec t ion is indicated for the treatment of symptomatic Paget’s disease of bone in patients with moderate to severe disease characterized by polyostotic involvement with elevated serum alkaline phosphatase and urinary hydroxyproline excretion. There is no evidence that the prophylactic use of calcitonin-salmon is beneficial in asymptomatic patients. Calcitonin-salmon injection should be used only in patients who do not respond to alternative treatments or for whom such treatments are not suitable (e.g., patients for whom other therapies are contraindicated or for patients who are intolerant or unwilling to use other therapies).

1.2 Treatment of Hypercalcemia Calcitonin-salmon injection is indicated for the early treatment of hypercalcemic emergencies, along with other appropriate agents, when a rapid decrease in serum calcium is required, until more specific treatment of the underlying disease can be accomplished. It may also be added to existing therapeutic regimens for hypercalcemia such as intravenous fluids and furosemide, oral phosphate or corticosteroids, or other agents.

1.3 Treatment of Postmenopausal Osteoporosis Calcitonin-salmon injection is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause. The evidence of efficacy for calcitonin-salmon injection is based on increases in total body calcium observed in clinical trials. Fracture reduction efficacy has not been demonstrated. Calcitonin-salmon injection should be reserved for patients for whom alternative treatments are not suitable (e.g., patients for whom other therapies are contraindicated or for patients who are intolerant or unwilling to use other therapies).

1.4 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span>.

1.1 Treatment of Paget&apos;s Disease of Bone Calcitonin-salmon injec t ion is indicated for the treatment of symptomatic Paget’s disease of bone in patients with moderate to severe disease characterized by polyostotic involvement with elevated serum alkaline phosphatase and urinary hydroxyproline excretion. There is no evidence that the prophylactic use of calcitonin-salmon is beneficial in asymptomatic patients. Calcitonin-salmon injection should be used only in patients who do not respond to alternative treatments or for whom such treatments are not suitable (e.g., patients for whom other therapies are contraindicated or for patients who are intolerant or unwilling to use other therapies).

1.2 Treatment of Hypercalcemia Calcitonin-salmon injection is indicated for the early treatment of hypercalcemic emergencies, along with other appropriate agents, when a rapid decrease in serum calcium is required, until more specific treatment of the underlying disease can be accomplished. It may also be added to existing therapeutic regimens for hypercalcemia such as intravenous fluids and furosemide, oral phosphate or corticosteroids, or other agents.

1.3 Treatment of Postmenopausal Osteoporosis Calcitonin-salmon injection is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause. The evidence of efficacy for calcitonin-salmon injection is based on increases in total body calcium observed in clinical trials. Fracture reduction efficacy has not been demonstrated. Calcitonin-salmon injection should be reserved for patients for whom alternative treatments are not suitable (e.g., patients for whom other therapies are contraindicated or for patients who are intolerant or unwilling to use other therapies).

1.4 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span>.

AND ADMINISTRATION

• Symptomatic Paget’s disease of bone: 100 International Units daily. Ensure adequate calcium and vitamin D intake ( 2.1 , 2.5 )
• Hypercalcemia: start with 4 International Units/kg body weight every 12 hours. Increase to 8 International Units/kg every 12 hours if no improvement in 1-2 days. Increase further to 8 International Units/kg every 6 hours if no improvement after 2 more days ( 2.2 )
• Postmenopausal osteoporosis: 100 International Units daily. Ensure adequate calcium and vitamin D intake ( 2.3 , 2.5 )

2.1 Paget&apos;s Disease of Bone The recommended dose of calcitonin-salmon injection for treatment of symptomatic Paget’s disease of bone is 100 International Units (0.5 mL) per day administered subcutaneously or intramuscularly.

2.2 Hypercalcemia The recommended starting dose of calcitonin-salmon injection for early treatment of hypercalcemia is 4 International Units/kg body weight every 12 hours by subcutaneous or intramuscular injection. If the response to this dose is not satisfactory after one or two days, the dose may be increased to 8 International Units/kg every 12 hours. If the response remains unsatisfactory after two more days, the dose may be further increased to a maximum of 8 International Units/kg every 6 hours.

2.3 Postmenopausal Osteoporosis The recommended dose of calcitonin-salmon injection for treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause is 100 International Units (0.5 mL) per day administered subcutaneously or intramuscularly. The minimum effective dose of calcitonin-salmon injection for the prevention of vertebral bone mineral density loss has not been established.

2.4 Preparation and Administration Visually inspect calcitonin-salmon vials. Calcitonin-salmon injection is a clear, colorless, solution. If the solution is not clear and colorless, or contains any particles, or if the vial is damaged, do not administer the solution. If the volume of calcitonin-salmon injection to be injected exceeds 2 mL, intramuscular injection is preferable and the total dose should be distributed across multiple sites of injection. Instruct patients to use sterile injection technique when administering calcitonin-salmon injection, and to dispose of needles properly.

2.5 Recommendations for Calcium and Vitamin D Supplementation Patients who use calcitonin-salmon injection for treatment of postmenopausal osteoporosis should receive adequate calcium (at least 1000 mg elemental calcium per day) and vitamin D (at least 400 International Units per day).

2.1 Paget&apos;s Disease of Bone The recommended dose of calcitonin-salmon injection for treatment of symptomatic Paget’s disease of bone is 100 International Units (0.5 mL) per day administered subcutaneously or intramuscularly.

2.2 Hypercalcemia The recommended starting dose of calcitonin-salmon injection for early treatment of hypercalcemia is 4 International Units/kg body weight every 12 hours by subcutaneous or intramuscular injection. If the response to this dose is not satisfactory after one or two days, the dose may be increased to 8 International Units/kg every 12 hours. If the response remains unsatisfactory after two more days, the dose may be further increased to a maximum of 8 International Units/kg every 6 hours.

2.3 Postmenopausal Osteoporosis The recommended dose of calcitonin-salmon injection for treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause is 100 International Units (0.5 mL) per day administered subcutaneously or intramuscularly. The minimum effective dose of calcitonin-salmon injection for the prevention of vertebral bone mineral density loss has not been established.

2.4 Preparation and Administration Visually inspect calcitonin-salmon vials. Calcitonin-salmon injection is a clear, colorless, solution. If the solution is not clear and colorless, or contains any particles, or if the vial is damaged, do not administer the solution. If the volume of calcitonin-salmon injection to be injected exceeds 2 mL, intramuscular injection is preferable and the total dose should be distributed across multiple sites of injection. Instruct patients to use sterile injection technique when administering calcitonin-salmon injection, and to dispose of needles properly.

2.5 Recommendations for Calcium and Vitamin D Supplementation Patients who use calcitonin-salmon injection for treatment of postmenopausal osteoporosis should receive adequate calcium (at least 1000 mg elemental calcium per day) and vitamin D (at least 400 International Units per day).

Hypersensitivity to calcitonin-salmon or any of the excipients. Reactions have included anaphylactic shock, anaphylaxis, bronchospasm, and swelling of the tongue or throat [see Warnings and Precautions ( 5.1 ) ]. Hypersensitivity to calcitonin-salmon or any of the excipients (4 )

REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Hypersensitivity Reactions, including anaphylaxis [see Warnings and Precautions ( 5.1 )] Hypocalcemia [see Warnings and Precautions ( 5.2 )] Malignancy [see Warnings and Precautions ( 5.3 )] Most common adverse reactions are nausea with or without vomiting (10%), injection site inflammation (10%), and flushing of the face or hands (2% to 5%) ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of calcitonin-salmon injection was assessed in open-label trials several months to two years in duration. The most common adverse reactions are discussed below. Nausea: Nausea with or without vomiting has been noted in about 10% of patients treated with calcitonin-salmon. It is most evident when treatment is first initiated and tends to decrease or disappear with continued administration.

Dermatologic

Reactions: Local inflammatory reactions at the site of subcutaneous or intramuscular injection have been reported in about 10% of patients. Flushing of face or hands occurred in about 2% to 5% of patients. Skin rashes and pruritus of the ear lobes have also been reported.

Other Adverse

Reactions: Nocturia, feverish sensation, pain in the eyes, poor appetite, abdominal pain, pedal edema, and salty taste have been reported in patients treated with calcitonin-salmon injection. 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 10,883 patients (6,151 treated with calcitonin-salmon and 4,732 treated with placebo). The overall incidence of malignancies reported in these 21 trials was higher among calcitonin-salmon-treated patients (254/6,151 or 4.1%) compared with placebo-treated patients (137/4,732 or 2.9%). Findings were similar when analyses were restricted to the 18 nasal spray only trials [calcitonin-salmon 122/2,712 (4.5%); placebo 30/1,309 (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 1). 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 1); 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 ( 5.3 )].

Table

1: Risk Difference for Malignancies in Calcitonin-Salmon-Treated Patients Compared with Placebo-Treated Patients 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 cellcarcinoma 0.5 (-0.1, 1.2) All (nasal spray only)

All

1.4 (0.3, 2.6) All (nasal spray only) Excluding basal cellcarcinoma 0.8 (-0.2, 1.8) 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.

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 injection. Allergic / Hypersensitivity Reactions : Serious hypersensitivity reactions have been reported in patients receiving calcitonin-salmon injection, e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock, and death due to anaphylaxis. Skin and subcutaneous tissue disorders : Urticaria Hypocalcemia: Hypocalcemia with tetany (i.e. muscle cramps, twitching) and seizure activity have been reported. Body as a Whole: influenza-like symptoms, fatigue, edema (facial, peripheral, and generalized) Musculoskeletal: arthralgia, musculoskeletal pain Cardiovascular: hypertension Gastrointestinal: abdominal pain, diarrhea Urinary System: polyuria Nervous System: dizziness, headache, paresthesia, tremor Vision: visual disturbance

6.3 Immunogenicity Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of calcitonin-salmon may trigger the development of anti-calcitonin antibodies. Circulating antibodies to calcitonin-salmon after 2 to 18 months of treatment have been reported in about one-half of the patients with Paget’s disease in whom antibody studies were done. In some cases, high antibody titers are found; these patients usually will have a loss of response to treatment <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span>. 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 among different calcitonin-salmon products may be misleading.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of calcitonin-salmon injection was assessed in open-label trials several months to two years in duration. The most common adverse reactions are discussed below. Nausea: Nausea with or without vomiting has been noted in about 10% of patients treated with calcitonin-salmon. It is most evident when treatment is first initiated and tends to decrease or disappear with continued administration.

Dermatologic

Reactions: Local inflammatory reactions at the site of subcutaneous or intramuscular injection have been reported in about 10% of patients. Flushing of face or hands occurred in about 2% to 5% of patients. Skin rashes and pruritus of the ear lobes have also been reported.

Other Adverse

Reactions: Nocturia, feverish sensation, pain in the eyes, poor appetite, abdominal pain, pedal edema, and salty taste have been reported in patients treated with calcitonin-salmon injection. 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 10,883 patients (6,151 treated with calcitonin-salmon and 4,732 treated with placebo). The overall incidence of malignancies reported in these 21 trials was higher among calcitonin-salmon-treated patients (254/6,151 or 4.1%) compared with placebo-treated patients (137/4,732 or 2.9%). Findings were similar when analyses were restricted to the 18 nasal spray only trials [calcitonin-salmon 122/2,712 (4.5%); placebo 30/1,309 (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 1). 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 1); 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 ( 5.3 )].

Table

1: Risk Difference for Malignancies in Calcitonin-Salmon-Treated Patients Compared with Placebo-Treated Patients 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 cellcarcinoma 0.5 (-0.1, 1.2) All (nasal spray only)

All

1.4 (0.3, 2.6) All (nasal spray only) Excluding basal cellcarcinoma 0.8 (-0.2, 1.8) 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.

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 injection. Allergic / Hypersensitivity Reactions : Serious hypersensitivity reactions have been reported in patients receiving calcitonin-salmon injection, e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock, and death due to anaphylaxis. Skin and subcutaneous tissue disorders : Urticaria Hypocalcemia: Hypocalcemia with tetany (i.e. muscle cramps, twitching) and seizure activity have been reported. Body as a Whole: influenza-like symptoms, fatigue, edema (facial, peripheral, and generalized) Musculoskeletal: arthralgia, musculoskeletal pain Cardiovascular: hypertension Gastrointestinal: abdominal pain, diarrhea Urinary System: polyuria Nervous System: dizziness, headache, paresthesia, tremor Vision: visual disturbance

6.3 Immunogenicity Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of calcitonin-salmon may trigger the development of anti-calcitonin antibodies. Circulating antibodies to calcitonin-salmon after 2 to 18 months of treatment have been reported in about one-half of the patients with Paget’s disease in whom antibody studies were done. In some cases, high antibody titers are found; these patients usually will have a loss of response to treatment <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span>. 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 among different calcitonin-salmon products may be misleading.

AND PRECAUTIONS

• Serious hypersensitivity reactions, including reports of fatal anaphylaxis have been reported. Consider skin testing prior to treatment in patients with suspected hypersensitivity to calcitonin-salmon ( 5.1 )
• Hypocalcemia has been reported. Ensure adequate intake of calcium and vitamin D ( 5.2 )
• Malignancy: A meta-analysis of 21 clinical trials suggests an increased risk of overall malignancies in calcitonin-salmon­ treated patients ( 5.3 , 6.1 )
• Circulating antibodies to calcitonin-salmon may develop, and may cause loss of response to treatment ( 5.4 )

5.1 Hypersensitivity Reactions Serious hypersensitivity reactions have been reported in patients receiving calcitonin-salmon injection, e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock, and death due to anaphylaxis. Appropriate medical support and monitoring measures should be readily available when calcitonin-salmon injection is administered. If anaphylaxis or other severe hypersensitivity/allergic reactions occur, initiate appropriate treatment <span class="opacity-50 text-xs">[see Contraindications ( 4) ]</span>. For patients with suspected hypersensitivity to calcitonin-salmon, skin testing should be considered prior to treatment utilizing a dilute, sterile solution of calcitonin-salmon injection. Healthcare providers may wish to refer patients who require skin testing to an allergist.A detailed skin testing protocol is available from the Dr. Reddy’s Laboratories Inc.

Medical

Service team.

5.2 Hypocalcemia Hypocalcemia associated with tetany (i.e., muscle cramps, twitching) and seizure activity has been reported with calcitonin-salmon injection therapy. Hypocalcemia must be corrected before initiating therapy. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients at risk for hypocalcemia, provisions for parenteral calcium administration should be available during the first several administrations of calcitonin­ salmon and serum calcium and symptoms of hypocalcemia should be monitored. Use of calcitonin-salmon injection for the treatment of Paget’s disease or postmenopausal osteoporosis is recommended in conjunction with an adequate intake of calcium and vitamin D <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5) ]</span>.

5.3 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. It is not possible to exclude an increased risk when calcitonin-salmon is administered long-term subcutaneously, intramuscularly, or intravenously. The benefits for the individual patient should be carefully considered against possible risks <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>.

5.4 Antibody Formation Circulating antibodies to calcitonin-salmon have been reported with calcitonin-salmon injection. The possibility of antibody formation should be considered in any patient with an initial response to calcitonin-salmon injection who later stops responding to treatment <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.3 )]</span>.

5.5 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.

5.1 Hypersensitivity Reactions Serious hypersensitivity reactions have been reported in patients receiving calcitonin-salmon injection, e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock, and death due to anaphylaxis. Appropriate medical support and monitoring measures should be readily available when calcitonin-salmon injection is administered. If anaphylaxis or other severe hypersensitivity/allergic reactions occur, initiate appropriate treatment <span class="opacity-50 text-xs">[see Contraindications ( 4) ]</span>. For patients with suspected hypersensitivity to calcitonin-salmon, skin testing should be considered prior to treatment utilizing a dilute, sterile solution of calcitonin-salmon injection. Healthcare providers may wish to refer patients who require skin testing to an allergist.A detailed skin testing protocol is available from the Dr. Reddy’s Laboratories Inc.

Medical

Service team.

5.2 Hypocalcemia Hypocalcemia associated with tetany (i.e., muscle cramps, twitching) and seizure activity has been reported with calcitonin-salmon injection therapy. Hypocalcemia must be corrected before initiating therapy. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients at risk for hypocalcemia, provisions for parenteral calcium administration should be available during the first several administrations of calcitonin­ salmon and serum calcium and symptoms of hypocalcemia should be monitored. Use of calcitonin-salmon injection for the treatment of Paget’s disease or postmenopausal osteoporosis is recommended in conjunction with an adequate intake of calcium and vitamin D <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5) ]</span>.

5.3 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. It is not possible to exclude an increased risk when calcitonin-salmon is administered long-term subcutaneously, intramuscularly, or intravenously. The benefits for the individual patient should be carefully considered against possible risks <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>.

5.4 Antibody Formation Circulating antibodies to calcitonin-salmon have been reported with calcitonin-salmon injection. The possibility of antibody formation should be considered in any patient with an initial response to calcitonin-salmon injection who later stops responding to treatment <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.3 )]</span>.

5.5 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.

INTERACTIONS No formal drug interaction studies have been performed with Calcitonin Salmon Nasal Solution. Concomitant use of calcitonin-salmon and lithium may lead to a reduction in plasma lithium concentrations due to increased urinary clearance of lithium. The dose of lithium may require adjustment. Concomitant use of calcitonin-salmon and lithium may lead to a reduction in plasma lithium concentrations due to increased urinary clearance of lithium. The dose of lithium may require adjustment ( 7 )