Calcitonin Salmon: Package Insert and Label Information (Page 2 of 2)

7 DRUG INTERACTIONS

No formal drug interaction studies have been performed with calcitonin salmon injection.

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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no studies with calcitonin salmon injection in pregnant women to inform a drug associated risk for birth defects or miscarriage. In an animal reproduction study, subcutaneous administration of calcitonin salmon to pregnant rabbits during organogenesis at 4-18 times the recommended parenteral human dose caused a decrease in fetal birth weights. No adverse developmental outcome was observed in the rat with subcutaneous administration of calcitonin salmon at 9 times the recommended human parenteral dose based on body surface area (see Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Calcitonin salmon has been shown to cause a decrease in fetal birth weights in rabbits when given by subcutaneous injection in doses 4 to 18 times the parenteral dose recommended for human use (of 54 International Units/m²).

No embryo/fetal toxicities related to calcitonin salmon injection 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

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. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Calcitonin salmon injection and any potential adverse effects on the breastfed infant from calcitonin salmon injection or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of calcitonin salmon injection did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

The pharmacologic actions of calcitonin salmon injection suggest that hypocalcemic tetany could occur in overdose. Therefore, provisions for parenteral administration of calcium should be available for the treatment of overdose.

A dose of calcitonin salmon l000 International Units subcutaneously may produce nausea and vomiting. Doses of 32 International Units per kg per day for 1 to 2 days demonstrate no other adverse effects. Data on chronic high-dose administration are insufficient to assess toxicity.

11 DESCRIPTION

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 Structural Formula

It is provided in sterile solution for subcutaneous or intramuscular injection. Each milliliter contains: calcitonin salmon 200 International Units.

Inactive Ingredients (per mL): acetic acid, USP, 2.25 mg; phenol, USP, 5.0 mg; sodium acetate trihydrate, USP, 2.0 mg; sodium chloride, USP, 7.5 mg; water for injection, USP.

The activity of calcitonin salmon injection 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Calcitonin salmon is a calcitonin receptor agonist. Calcitonin salmon acts primarily on bone, but direct renal effects and actions on the gastrointestinal tract are also recognized. Calcitonin salmon appears to have actions essentially identical to calcitonins of mammalian origin, but its potency per mg is greater and it has a longer duration of action.

The actions of calcitonin on bone and its role in normal human bone physiology are still not completely elucidated, although calcitonin receptors have been discovered in osteoclasts and osteoblasts.

12.2 Pharmacodynamics

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.

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.

12.3 Pharmacokinetics

The absolute bioavailability of calcitonin salmon is approximately 66% and 71% after intramuscular or subcutaneous injection, respectively. After subcutaneous administration, peak plasma levels are reached in approximately 23 minutes. The terminal half-life is approximately 58 minutes for intramuscular administration and 59 to 64 minutes for subcutaneous administration. The apparent volume of distribution is 0.15 to 0.3 L/kg.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 1/6^th 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.

14 CLINICAL STUDIES

14.1 Paget’s Disease of Bone

The trials used for the basis of approval for calcitonin salmon injection for treatment of Paget’s disease of bone were conducted in patients with moderate to severe disease characterized by polyostotic involvement with elevated serum alkaline phosphatase and urinary hydroxyproline excretion. In open-label clinical trials of several months to two years duration with historical controls, biochemical abnormalities were substantially improved (more than 30% reduction) in about 2/3 of patients studied and bone pain was improved in a similar fraction. A small number of documented instances of reversal of neurologic deficits have occurred, including improvement in the basilar compression syndrome, and improvement of spinal cord and spinal nerve lesions. There is too little experience to predict the likelihood of improvement of any given neurologic lesion. Hearing loss is improved infrequently (4 of 29 patients studied by audiometry). Patients with increased cardiac output due to extensive Paget’s disease of bone have had measured decreases in cardiac output while receiving calcitonin salmon. The number of treated patients in this category is too small to predict how likely such a result will be.

There is no evidence that the prophylactic use of calcitonin salmon is beneficial in asymptomatic patients.

14.2 Hypercalcemia

In four open-label clinical trials enrolling 53 patients, calcitonin salmon has been shown to lower elevated serum calcium levels of patients with carcinoma (with or without metastases), multiple myeloma, and primary hyperparathyroidism (lesser response). These patients were treated with calcitonin salmon only when other methods of lowering serum calcium (hydration, oral phosphate, corticosteroids) were unsuccessful or unsuitable. With patients’ pre-therapy serum calcium levels as controls, reduction in serum calcium was evident within 1 to 2 hours of administration. The peak effect occurred within 24 to 48 hours of injection and administration of calcitonin salmon every 12 hours maintained a hypocalcemic effect for approximately 5 to 8 days, the time period evaluated for most patients in the clinical trials. The average reduction of 8-hour post-injection serum calcium was approximately 9% (2 to 3 mg/dL). Patients with higher values of serum calcium tended to show greater reductions during calcitonin salmon treatment.

14.3 Postmenopausal Osteoporosis

The trials used for the basis of approval for calcitonin salmon injection for treatment of postmenopausal osteoporosis were two randomized, open-label, 2-year studies in postmenopausal women 50 to 74 years of age with total body calcium <85% of expected normal, and vertebral osteopenia (by x-ray criteria) and/or at least one atraumatic compression fracture. The primary efficacy endpoint was total body calcium measured by neutron activation analysis. Patients were randomized to calcitonin salmon injection 100 International Units daily (subcutaneously or intramuscularly) at bedtime, or control. All subjects received daily supplements of 1200 mg calcium carbonate and 400 International Units of vitamin D.

In both studies, total body calcium increased from baseline with calcitonin salmon therapy at 1 year, followed by a trend to decreasing total body calcium (still above baseline) at 2 years.

Thoracic and lumbar spine X-rays (AP/lateral) were obtained yearly. For the two studies combined (34 calcitonin salmon and 35 control subjects), in the first year there was a total of 6 new vertebral compression fractures in the calcitonin salmon group and 5 in the control group. In the second year there were 7 new fractures in each group.

No evidence currently exists to indicate whether calcitonin salmon injection decreases the risk of osteoporotic fracture. A controlled study, which was prematurely discontinued, failed to demonstrate any benefit of calcitonin salmon on fracture rate.

No adequate controlled trials have examined the effect of calcitonin salmon injection on vertebral bone mineral density beyond 1 year of treatment. Therefore, the minimum effective dose of calcitonin salmon injection for prevention of vertebral bone mineral density loss has not been established.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Calcitonin Salmon Injection, USP, Synthetic is available as a sterile solution in individual 2 mL multi-dose vials containing 200 International Units per mL …………………..NDC 42023-205-01

Storage and Handling

Store in refrigerator between 2° to 8°C (36° to 46°F).

Avoid Freezing.

17 PATIENT COUNSELING INFORMATION

• Instruct patients and other persons who may administer calcitonin salmon injection in sterile injection technique. Also instruct patients to dispose of needles properly [see Dosage and Administration (2.4)].
• Inform patients of the potential increase in risk of malignancy [see Warnings and Precautions (5.3)].
• Advise patients with postmenopausal osteoporosis or Paget’s disease of bone to maintain an adequate calcium (at least 1000 mg elemental calcium per day) and vitamin D (at least 400 International Units per day) intake [see Dosage and Administration (2.5)].
• Instruct patients to seek emergency medical help or go to the nearest hospital emergency room right away if they develop any signs or symptoms of a serious allergic reaction [see Warnings and Precautions (5.1)].

Distributed by:

Par Pharmaceutical

Chestnut Ridge, NY 10977

I10/17

OS205J-01-90-01

3003663A

PRINCIPAL DISPLAY PANEL – 400 I.U. per 2 mL

Calcitonin Salmon Injection — Carton

CALCITONIN SALMON calcitonin salmon injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42023-205 Route of Administration INTRAMUSCULAR, SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CALCITONIN SALMON (CALCITONIN SALMON) CALCITONIN SALMON 200 [iU] in 1 mL

Inactive Ingredients Ingredient Name Strength ACETIC ACID 2.25 mg in 1 mL PHENOL 5 mg in 1 mL SODIUM ACETATE 2 mg in 1 mL SODIUM CHLORIDE 7.5 mg in 1 mL WATER

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:42023-205-01 1 VIAL, MULTI-DOSE in 1 CARTON contains a VIAL, MULTI-DOSE 1 2 mL in 1 VIAL, MULTI-DOSE This package is contained within the CARTON (42023-205-01)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA209358 11/10/2021

Labeler — Par Pharmaceutical, Inc. (092733690)

Revised: 10/2017 Par Pharmaceutical, Inc.