CALCITONIN SALMON spray, metered
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1. Patient Information
2. What Is Calcitonin Salmon (synthetic Origin) Nasal Spray?
3. Do Not Use Calcitonin Salmon (synthetic Origin) Nasal Spray If You:
4. Before You Use Calcitonin Salmon (synthetic Origin) Nasal Spray, Tell Your Healthcare Provider If You:
5. Especially Tell Your Healthcare Provider If You Take:
6. How Should I Use Calcitonin Salmon (synthetic Origin) Nasal Spray?
7. Calcitonin Salmon (synthetic Origin) Nasal Spray May Cause Serious Side Effects, Including:
8. The Most Common Side Effects Of Calcitonin Salmon (synthetic Origin) Nasal Spray Include:
9. How Do I Store Calcitonin Salmon (synthetic Origin) Nasal Spray?
10. Active Ingredients:
11. Inactive Ingredients:

Patient Information ⮝

See FDA-approved patient labeling (Patient Information and Instructions for Use).

• Instruct patients on pump assembly, priming of the pump, and nasal introduction of Calcitonin Salmon (synthetic origin) Nasal Spray. Although instructions for patients are supplied with the individual bottle, procedures for use should be demonstrated to each patient[see Dosage and Administration (2.2)]. Patients should notify their healthcare provider if they develop significant nasal irritation[see Warnings and Precautions (5.3)].
• Inform patients of the potential increase in risk of malignancy[see Warnings and Precautions (5.4)].
• Advise patients 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 (2.3)].
• 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.
• 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

What Is Calcitonin Salmon (synthetic Origin) Nasal Spray? ⮝

Calcitonin Salmon (synthetic origin) Nasal Spray is a prescription medicine used to treat osteoporosis in women more than 5 years after menopause. Calcitonin Salmon (synthetic origin) Nasal Spray should be used for women who cannot use other treatments or who choose not to use other treatments for osteoporosis.

It is not known if Calcitonin Salmon (synthetic origin) Nasal Spray lowers the chance of having bone fractures.

Calcitonin Salmon (synthetic origin) Nasal Spray has not been shown to be effective in women less than 5 years after menopause.

It is not known if Calcitonin Salmon (synthetic origin) Nasal Spray is safe and effective in children under 18 years of age.

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.

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,

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.

Active Ingredients: ⮝

calcitonin salmon

Inactive Ingredients: ⮝

benzalkonium chloride, hydrochloric acid, purified water and sodium chloride.

1. No Title 1572552109
2. Description
3. Clinical Pharmacology
4. Indications And Usage
5. Contraindications
6. Warnings
7. Precautions
8. Adverse Reactions
9. Overdosage
10. Dosage And Administration
11. How Supplied
12. Information For The Patient
13. How To Assemble And Use
14. Principal Display Panel - Carton
15. Highlights Of Prescribing Information
16. Dosage Forms And Strengths
17. Warnings And Precautions
18. Drug Interactions
19. Use In Specific Populations
20. 1 Indications And Usage
21. 2 Dosage And Administration
22. 3 Dosage Forms And Strengths
23. 4 Contraindications
24. 5 Warnings And Precautions
25. 6 Adverse Reactions
26. 7 Drug Interactions
27. 8 Use In Specific Populations
28. 10 Overdosage
29. 11 Description
30. 12 Clinical Pharmacology
31. 13 Nonclinical Toxicology
32. 14 Clinical Studies
33. 16 How Supplied/storage And Handling
34. Instructions For Use
35. Principal Display Panel
36. Recent Major Changes
37. Information For The Patient
38. Package/label Principal Display Panel
39. 1 Indications And Usage
40. 2 Dosage And Administration
41. 3 Dosage Forms And Strengths
42. 4 Contraindications
43. 5 Warnings And Precautions
44. 6 Adverse Reactions
45. 7 Drug Interactions
46. 8 Use In Specific Populations
47. 10 Overdosage
48. 11 Description
49. 12 Clinical Pharmacology
50. 13 Nonclinical Toxicology
51. 14 Clinical Studies
52. 16 How Supplied/storage And Handling
53. No Title 1572457517

No Title 1572552109 ⮝

Instructions for Use

Calcitonin-Salmon Nasal Spray

For Nasal Use Only.

Important information about your calcitonin-salmon:

• A single spray of calcitonin-salmon nasal spray contains 1 daily dose of medicine.
• Each calcitonin-salmon bottle contains the right amount of medicine. The bottle may not be completely filled to the top. This is normal.
• This package contains 1 bottle of calcitonin-salmon and 1 screw-on pump. See Figure A.
• Store unopened bottles of calcitonin-salmon in the refrigerator between 36 F to 46 F (2 C to 8 C). Do not freeze.
• After you open your bottle of calcitonin-salmon, store it at room temperature between 59 F to 86 F (15 C to 30 C) in an upright position. Do not shake the bottle.

Figure A

	Preparing your calcitonin-salmon: Step 1. Remove the bottle from your refrigerator and let it reach room temperature. Check the medicine in the bottle to make sure it is clear and colorless without particles. Important: If your calcitonin-salmon bottle and pump has already been put together by your pharmacist or healthcare provider, go to Step 7.
Figure B	Step 2. Lift up the blue plastic tab and carefully pull the metal safety seal off the bottle. See Figure B.
Figure C	Step 3. Keep the bottle upright and remove the rubber stopper from the bottle. See Figure C.
Figure D	Step 4. Hold the nose spray pump and gently remove the plastic protective cap from the bottom of the nose spray pump. See Figure D. Do not push down on the pump when it is not attached to the bottle.
Figure E	Step 5. Hold the bottle upright and insert the nose spray pump into the bottle. Turn the pump clockwise to tighten it until it is securely attached to the bottle. See Figure E.
Figure F	Step 6. Gently pull the clear protective cap to remove it from the top of the nose spray pump. See Figure F.
Figure G	Step 7. Check to see if your calcitonin-salmon has been primed. To make sure you get the right dose of calcitonin-salmon medicine you must prime each new bottle and pump before you use it for the first time. If your pharmacist or healthcare provider puts the bottle and pump together for you, check to see if it has already been primed by pressing on the pump 1 time. See Figure G. If you see a full spray from the pump, the bottle and pump has already been primed for you. If you do not see a full spray, you must prime the bottle and pump. Step 8. Priming your calcitonin-salmon: Hold the bottle upright with your pointer finger and middle finger on the 2 side arms of the pump, and your thumb on the bottom of the bottle. Firmly press down on the arms of the pump and press down again if needed until you see a full spray of medicine. See Figure G. Now your calcitonin-salmon is ready for you to use. Do not prime the pump before you use it each day because this will waste your medicine.
Figure H	Giving your calcitonin-salmon dose: Step 9. Insert the nasal spray pump in 1 side of your nose. See Figure H. Keep your head upright. Carefully tilt the bottle and place the nose spray pump into 1 side of your nose.
Figure I	Step 10. Firmly press down on the nose spray pump to release the medicine. See Figure I. Give 1 spray of calcitonin-salmon, 1 time daily, in 1 side of your nose (nostril). Spray your medicine in a different side of your nose each day. You do not need to breathe in or inhale while you are giving your dose. You may not feel the spray inside your nose. Some of the medicine may drip out of your nose. This is normal, and you are still getting all of the medicine you need.
Figure J	Cleaning your calcitonin-salmon pump: Step 11. Wipe the nose spray pump with a clean, damp cloth 1 to 2 times a week. See Figure J. Dry the nose spray pump with a clean cloth.
Figure K	Storing your calcitonin-salmon: Step 12. Gently put the protective cap back on the nasal spray pump. Hold the bottle with 2 fingers under the 2 side arms of the pump. See Figure K. Be careful not push down on the pump while you are putting the cap back on it. Do not refrigerate calcitonin-salmon between doses. Store calcitonin-salmon upright. Do not shake the bottle.

When should I throw away calcitonin-salmon?

• Unopened, refrigerated bottles can be used until the expiration date stamped on the bottle and box.
• Throw away calcitonin-salmon after you use 30 doses (sprays).
• Throw away calcitonin-salmon bottles left at room temperature (opened or unopened) for more than 35 days.

For more information on calcitonin-salmon nasal spray and how to put it together, call Sandoz Inc. at 1-800-525-8747.

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Distributed by:
Sandoz Inc.
Princeton, NJ 08540

T2014-36/T2014-37
March 2014/March 2014

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 Nasal Spray 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:

It is provided in 3.7 mL fill glass bottles as a solution for nasal administration. This is sufficient medication for at least 30 doses.

Active Ingredient:calcitonin-salmon, 2200 I.U. per mL (corresponding to 200 I.U. per 0.09 mL actuation).

Inactive Ingredients:sodium chloride, chlorobutanol, hydrochloric acid (added as necessary to adjust pH), purified water and nitrogen.

The activity of Calcitonin-Salmon Nasal Spray 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 of Biologic Standards and Control, Holly Hill, London.

Clinical Pharmacology ⮝

Calcitonin 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 information below, describing the clinical pharmacology of calcitonin, has been derived from studies with injectable calcitonin. The mean bioavailability of Calcitonin-Salmon Nasal Spray is approximately 3% of that of injectable calcitonin in normal subjects and, therefore, the conclusions concerning the clinical pharmacology of this preparation may be different.

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.

Single injections of calcitonin cause 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 vitro studies have shown that calcitonin-salmon causes inhibition of osteoclast function with loss of the ruffled osteoclast border responsible for resorption of bone. This activity resumes following removal of calcitonin-salmon from the test system. There is some evidence from the in vitro studies that bone formation may be augmented by calcitonin through increased osteoblastic activity.

Animal studies indicate that endogenous calcitonin, primarily through its action on bone, participates with parathyroid hormone in the homeostatic regulation of blood calcium. Thus, high blood calcium levels cause increased secretion of calcitonin which, in turn, inhibits bone resorption. This reduces the transfer of calcium from bone to blood and tends to return blood calcium towards the normal level. The importance of this process in humans has not been determined. In normal adults, who have a relatively low rate of bone resorption, the administration of exogenous calcitonin results in only a slight decrease in serum calcium in the limits of the normal range. In normal children and in patients with Paget s disease in whom bone resorption is more rapid, decreases in serum calcium are more pronounced in response to calcitonin.

Bone biopsy and radial bone mass studies at baseline and after 26 months of daily injectable calcitonin indicate that calcitonin therapy results in formation of normal bone.

Postmenopausal Osteoporosis

Osteoporosis is a disease characterized by low bone mass and architectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk as patients approach or fall below a bone mineral density associated with increased frequency of fracture. The most common type of osteoporosis occurs in postmenopausal females. Osteoporosis is a result of a disproportionate rate of bone resorption compared to bone formation which disrupts the structural integrity of bone, rendering it more susceptible to fracture. The most common sites of these fractures are the vertebrae, hip, and distal forearm (Colles fractures). Vertebral fractures occur with the highest frequency and are associated with back pain, spinal deformity and a loss of height.

Calcitonin-Salmon Nasal Spray, given by the intranasal route, has been shown to increase spinal bone mass in post-menopausal women with established osteoporosis but not in early postmenopausal women.

Calcium Homeostasis

In two clinical studies designed to evaluate the pharmacodynamic response to Calcitonin-Salmon Nasal Spray, administration of 100-1600 I.U. to healthy volunteers resulted in rapid and sustained small decreases (but still within the normal range) in both total serum calcium and serum ionized calcium. Single doses greater than 400 I.U. did not produce any further biological response to the drug. The development of hypocalcemia has not been reported in studies in healthy volunteers or postmenopausal females.

Kidney

Studies with injectable calcitonin show increases in the excretion of filtered phosphate, calcium, and sodium by decreasing their tubular reabsorption. Comparable studies have not been carried out with Calcitonin-Salmon Nasal Spray.

Gastrointestinal Tract

Some evidence from studies with injectable preparations suggest that calcitonin may have significant actions on the gastrointestinal tract. Short-term administration of injectable calcitonin 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 during chronic therapy has not been investigated. These studies have not been conducted with Calcitonin-Salmon Nasal Spray.

Pharmacokinetics and Metabolism

The bioavailability of Calcitonin-Salmon Nasal Spray relative to intramuscular administration is between 3 and 5%. Calcitonin-Salmon Nasal Spray is absorbed by the nasal mucosa with a mean Tmax 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. Plasma exposure was higher following administration of 400 IU nasal spray compared to that after 200 IU dose. As is the case with other polypeptide hormones, there is very little value in monitoring plasma levels of salmon calcitonin since these are not directly predictive of the therapeutic response. Hence, Calcitonin-Salmon activity should be evaluated by using clinical parameters of efficacy.

Indications And Usage ⮝

Calcitonin Salmon (synthetic origin) Nasal Spray is a calcitonin, indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause when alternative treatments are not suitable. Fracture reduction efficacy has not been demonstrated (1.1)

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 (1.2, 5.4)
• Calcitonin salmon nasal spray has not been shown to increase bone mineral density in early postmenopausal women (1.2)

Contraindications ⮝

Hypersensitivity to calcitonin salmon or any of the excipients (4)

Warnings ⮝

Allergic Reactions

Because calcitonin is a polypeptide, the possibility of a systemic allergic reaction exists. A few cases of serious allergic-type reactions have been reported in patients receiving Calcitonin-Salmon Nasal Spray, including cases of anaphylaxis and anaphylactic shock. With injectable calcitonin-salmon there have been a few reports of serious allergic-type reactions (e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock), including very rare reports of death attributed to anaphylaxis. The usual provisions should be made for the emergency treatment of such a reaction should it occur. Allergic reactions should be differentiated from generalized flushing and hypotension.

For patients with suspected sensitivity to calcitonin, skin testing should be considered prior to treatment utilizing a dilute, sterile solution of calcitonin-salmon injection. Physicians may wish to refer patients who require skin testing to an allergist. A detailed skin testing protocol is available from the Drug Safety Department of Par Pharmaceutical Companies Inc. at 1-800-828-9393.

Precautions ⮝

Drug Interactions

Formal studies designed to evaluate drug interactions with calcitonin-salmon have not been done. No drug interaction studies have been performed with Calcitonin-Salmon Nasal Spray ingredients.

Concomitant use of calcitonin and lithium may lead to a reduction in plasma lithium concentrations due to increased urinary clearance of lithium. The dose of lithium may need to be adjusted.

The effects of prior use of diphosphonates in postmenopausal osteoporosis patients have not been assessed; however, in patients with Paget s disease, prior diphosphonate use appears to reduce the anti-resorptive response to Calcitonin-Salmon Nasal Spray.

Periodic Nasal Examinations

Periodic nasal examinations with visualization of the nasal mucosa, turbinates, septum and mucosal blood vessel status are recommended.

The development of mucosal alterations or transient nasal conditions occurred in up to 9% of patients who received Calcitonin-Salmon Nasal Spray and in up to 12% of patients who received placebo nasal spray in studies in postmenopausal females. The majority of patients (approximately 90%) in whom nasal abnormalities were noted also reported nasally related complaints/symptoms as adverse events. Therefore, a nasal examination should be performed prior to start of treatment with nasal calcitonin and at any time nasal complaints occur.

In all postmenopausal patients treated with Calcitonin-Salmon Nasal Spray, the most commonly reported nasal adverse events included rhinitis (12%), epistaxis (3.5%), and sinusitis (2.3%). Smoking was shown not to have any contributory effect on the occurrence of nasal adverse events. One patient (0.3%) treated with Calcitonin-Salmon Nasal Spray who was receiving 400 I.U. daily developed a small nasal wound. In clinical trials in another disorder (Paget s disease), 2.8% of patients developed nasal ulcerations.

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, Calcitonin-Salmon Nasal Spray should be discontinued. Although smaller ulcers often heal without withdrawal of Calcitonin-Salmon Nasal Spray, medication should be discontinued temporarily until healing occurs.

Information for Patients

Careful instructions on pump assembly, priming of the pump and nasal introduction of Calcitonin-Salmon Nasal Spray should be given to the patient. Although instructions for patients are supplied with individual bottles, procedures for use should be demonstrated to each patient. Patients should notify their physician if they develop significant nasal irritation.

Patients should be advised of the following:

• Store new, unassembled bottles in the refrigerator between 2 C-8 C (36 F-46 F).
• Protect the product from freezing.
• Before priming the pump and using a new bottle, allow it to reach room temperature.
• Store bottle in use at room temperature 20 C to 25 C (68 F to 77 F) in an upright position, for up to 35 days. Each bottle contains at least 30 doses.
• See DOSAGE AND ADMINISTRATION, Priming (Activation) of Pump for complete instructions on priming the pump and administering Calcitonin-Salmon Nasal Spray.

You should keep track of the number of doses used from the bottle.

After 30 doses, each spray may not deliver the correct amount of medication, even if the bottle is not completely empty.

Carcinogenicity and Mutagenicity and Impairment of Fertility

An increased incidence of non-functioning pituitary adenomas has been observed in one-year toxicity studies in Sprague-Dawley and Fischer 344 Rats administered (subcutaneously) calcitonin-salmon at dosages of 80 I.U. per kilogram per day (16-19 times the recommended human parenteral dose and about 130-160 times the human intranasal dose based on body surface area). The findings suggest that calcitonin-salmon reduced the latency period for development of pituitary adenomas that do not produce hormones, probably through the perturbation of physiologic processes involved in the evolution of this commonly occurring endocrine lesion in the rat. Although administration of calcitonin- salmon reduces the latency period of the development of nonfunctional proliferative lesions in rats, it did not induce the hyperplastic/neoplastic process.

Calcitonin-salmon was tested for mutagenicity using Salmonella typhimurium (5 strains) and Escherichia coli (2 strains), with and without rat liver metabolic activation, and found to be non-mutagenic. The drug was also not mutagenic in a chromosome aberration test in mammalian V79 cells of the Chinese Hamster in vitro.

Laboratory Tests

Urine sediment abnormalities have not been reported in ambulatory volunteers treated with Calcitonin-Salmon Nasal Spray. Coarse granular 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 evidence of renal abnormality and the urine sediment became normal after calcitonin was stopped. Periodic examinations of urine sediment should be considered.

Pregnancy

Teratogenic Effects

Category C

Calcitonin-salmon has been shown to cause a decrease in fetal birth weights in rabbits when given by injection in doses 8-33 times the parenteral dose and 70-278 times the intranasal dose recommended for human use based on body surface area.

Since calcitonin does not cross the placental barrier, this finding may be due to metabolic effects on the pregnant animal. There are no adequate and well controlled studies in pregnant women with calcitonin-salmon. Calcitonin-Salmon Nasal Spray is not indicated for use in pregnancy.

Nursing Mothers

It is not known whether this drug is excreted in human milk. As a general rule, nursing should not be undertaken while a patient is on this drug since many drugs are excreted in human milk. Calcitonin has been shown to inhibit lactation in animals.

Pediatric Use

There are no data to support the use of Calcitonin-Salmon Nasal Spray in children. Disorders of bone in children referred to as idiopathic juvenile osteoporosis have been reported rarely. The relationship of these disorders to postmenopausal osteoporosis has not been established and experience with the use of calcitonin in these disorders is very limited.

Geriatric Use

In one large 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 and over. Compared to subjects less than 65 years old, the incidence of nasal adverse events (rhinitis, irritation, erythema, and excoriation) was higher in patients over the age of 65, particularly those over the age of 75. Most events were mild in intensity. 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.

Adverse Reactions ⮝

Most common adverse reactions (3% or greater) are rhinitis, epistaxis and other nasal symptoms, back pain, arthralgia, and headache (6)

To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Overdosage ⮝

No instances of overdose with Calcitonin-Salmon Nasal Spray have been reported and no serious adverse reactions have been associated with high doses. There is no known potential for drug abuse for calcitonin-salmon.

Single doses of Calcitonin-Salmon Nasal Spray up to 1600 I.U., doses up to 800 I.U. per day for 3 days and chronic administration of doses up to 600 I.U. per day have been studied without serious adverse effects. A dose of 1000 I.U. of Calcitonin-Salmon injectable solution given subcutaneously may produce nausea and vomiting. A dose of Calcitonin-Salmon injectable solution of 32 I.U. per kg per day for 1 or 2 days demonstrated no additional adverse effects.

There have been no reports of hypocalcemic tetany. However, the pharmacologic actions of Calcitonin-Salmon Nasal Spray suggest that this could occur in overdose. Therefore, provisions for parenteral administration of calcium should be available for the treatment of overdose.

Dosage And Administration ⮝

• For intranasal use only: one spray (200 USP Calcitonin Salmon Units) per day, alternating nostrils daily (2.1)
• Prior to first use, allow the bottle to reach room temperature and prime the pump (2.2)
• Ensure adequate calcium and vitamin D intake (2.3)

How Supplied ⮝

Calcitonin-Salmon Nasal Spray, USP

Available as a metered dose clear solution in a 3.7 mL fill clear glass bottle. It is available in a dosage strength of 200 I.U. per activation (0.09 mL/spray). A screw-on pump is provided. The pump, following priming, will deliver 0.09 mL of solution. Calcitonin-Salmon Nasal Spray contains 2200 I.U./mL calcitonin-salmon and is provided in an individual box containing one glass bottle and one screw-on pump (NDC 54868-6323-0).

Store and Dispense

Store unopened bottle in refrigerator between 2 C-8 C (36 F-46 F). Protect from freezing.

Store bottle in use at room temperature between 20 C-25 C (68 F-77 F) in an upright position, for up to 35 days. Each bottle contains at least 30 doses.

Information For The Patient  ⮝

Calcitonin-Salmon Nasal Spray, USP

What is CALCITONIN-SALMON Nasal Spray?

CALCITONIN-SALMON Nasal Spray is a medication used for the treatment of osteoporosis after menopause (postmenopausal osteoporosis) in women more than 5 years after menopause with low bone mass who refuse or cannot tolerate estrogens, or in whom estrogens are not an option. Patients who use CALCITONIN-SALMON Nasal Spray should be sure to ingest adequate amounts of calcium and vitamin D along with therapy.

How much calcium and vitamin D do I need each day?

When taking CALCITONIN-SALMON Nasal Spray, it is recommended that you get at least 1000 mg of calcium and 400 I.U. (international units) of vitamin D each day. Check with your doctor or healthcare provider to see if you are getting enough calcium and vitamin D in your diet. If not, he or she may recommend that you start taking calcium and vitamin D supplements.

What is osteoporosis after menopause? What causes it?

Postmenopausal osteoporosis is a condition associated with frail, brittle bones. It usually occurs when "old" bone cells are removed from bones faster than they can be replaced by "new" bone cells. As a result, bones get weak and may become susceptible to fractures.

Osteoporosis occurs most frequently in women who have gone through menopause. At menopause, a woman s body goes through many changes, including a substantial decrease in the amount of estrogen produced. Estrogen in your body helps keep bones strong without it, they may become weak.

Postmenopausal osteoporosis begins without notice; however, over time symptoms develop such as:

• Curved spine
• Rounded shoulders
• Loss of height

Untreated, postmenopausal osteoporosis can be painful and disabling. Some women with postmenopausal osteoporosis suffer from broken hips and fractured wrists. Fortunately, osteoporosis after menopause is treatable. Your doctor or healthcare provider can prescribe a medication, like CALCITONIN-SALMON Nasal Spray, to treat your condition.

How does CALCITONIN-SALMON Nasal Spray work?

The active ingredient in CALCITONIN-SALMON Nasal Spray is calcitonin, a man-made protein similar to one found in people, other mammals, and some types of fish and birds.

The way calcitonin affects bone is still being studied, but it is believed to work in the following ways:

• Calcitonin reduces the activity of osteoclasts [AHS-tee-oh-clasts], the cells that remove "old" bone
• Because bone building continues while bone removal is slowed down, the result is an increase in bone mass

When you spray CALCITONIN-SALMON Nasal Spray into your nostril, it is rapidly absorbed by the blood vessels lining your nasal passages. It then travels into your bloodstream and on to your bones where it works to stop bone loss and helps your bones become stronger.

How do I use CALCITONIN-SALMON Nasal Spray?

The recommended dose of CALCITONIN-SALMON Nasal Spray is one spray daily in alternated nostrils unless directed otherwise by your healthcare provider. Start with a spray in the left nostril on your first day, followed by a spray in the right nostril on the second day. Continue to alternate nostrils every day. There are at least 30 "doses" of CALCITONIN-SALMON Nasal Spray in each bottle.

You should keep track of the number of doses used from the bottle.

After 30 doses, each spray may not deliver the correct amount of medication, even if the bottle is not completely empty.

Who should not take CALCITONIN-SALMON Nasal Spray?

CALCITONIN-SALMON Nasal Spray should not be used by patients who are allergic to the protein calcitonin-salmon, or by women who are pregnant or nursing.

You should be aware of these warnings and precautions when taking CALCITONIN-SALMON Nasal Spray.

• No formal studies designed to test drug interactions with calcitonin-salmon have been done; however, no drug interactions have been observed with the use of CALCITONIN-SALMON Nasal Spray. You should inform your doctor and pharmacist about the other prescription and nonprescription medications you are taking.
• In clinical studies, nasal symptoms occurred in approximately 9% of postmenopausal patients taking CALCITONIN-SALMON Nasal Spray. For this reason, it is recommended that a nasal examination be performed prior to the start of treatment and at any time nasal complaints occur.
• Rare instances of nasal ulceration have occurred with CALCITONIN-SALMON Nasal Spray. In some cases, your doctor may decide to temporarily discontinue treatment with CALCITONIN-SALMON Nasal Spray until symptoms subside.
• Because calcitonin-salmon is a protein, the possibility of a systemic allergic reaction exists. Patients who are allergic to calcitonin-salmon should not use CALCITONIN-SALMON Nasal Spray.
• CALCITONIN-SALMON Nasal Spray is safe to use in elderly patients. A slight increase in nasal symptoms has been observed in patients over 65 years of age; however, the symptoms are usually mild. No other unusual side effects have been seen in patients over 65 years of age.

Possible Side Effects

Most patients tolerate treatment with CALCITONIN-SALMON Nasal Spray very well; however, like all prescription drugs, CALCITONIN-SALMON Nasal Spray may cause some side effects in some people. These side effects are usually mild and generally do not lead to discontinuation of treatment with CALCITONIN-SALMON Nasal Spray. The most commonly reported side effects are:

• Nasal symptoms such as runny nose, crusting, or nasal bleeding
• Back/joint pain
• Headache

Anytime you have a medical problem you think may be related to CALCITONIN-SALMON Nasal Spray, talk to your doctor or healthcare provider.

Your doctor or pharmacist can demonstrate how to assemble, prime, and use CALCITONIN-SALMON Nasal Spray. In addition, detailed directions can be found in your CALCITONIN-SALMON Nasal Spray box. Please read them carefully before assembling and using the spray.

This medication is prescribed for a particular condition. Do not use it for another condition or give the drug to others. Keep CALCITONIN-SALMON Nasal Spray and all medicines out of reach of children. This leaflet provides a summary of information about CALCITONIN-SALMON Nasal Spray. If you have any questions or concerns about either CALCITONIN-SALMON Nasal Spray or osteoporosis, talk to your doctor. In addition, talk to your pharmacist or other healthcare provider.

How To Assemble And Use ⮝

CALCITONIN-SALMON NASAL SPRAY, USP

One Spray, Once a Day

BEFORE USING CALCITONIN-SALMON NASAL SPRAY

This package contains one bottle of Calcitonin-Salmon Nasal Spray and one screw on pump.

Important Facts About Your Medication

• The bottle contains the proper amount of medication be aware that the entire bottle will not be filled with liquid.
• Before opening and assembling your medication bottle, keep it in your refrigerator between 2 C to 8 C (36 F to 46 F). Do not freeze.
• After opening and assembling a new medication bottle, keep it at room temperature between 20 C to 25 C (68 F to 77 F) in an upright position.

HOW TO USE CALCITONIN-SALMON NASAL SPRAY

Putting the Nasal Spray Pump Unit Together

1. If your bottle and pump unit were already assembled by your pharmacist, go to step 6. If not, remove the bottle from your refrigerator and allow it to reach room temperature before assembling.

2. Keeping the bottle upright, unscrew the white cap.

3. Remove the pump from the plastic protection bag.

4. Holding the bottle upright, insert the nasal spray pump unit into the bottle. Then turn the pump clockwise, and tighten it until it is securely fastened to the bottle.

Note: Do not depress pump when it is not attached to the bottle.

5. Holding the bottle upright with your index finger on top of one of the two side arms of the pump, gently remove the clear protective cap from the top of the nozzle.

Priming a New Bottle

6. To ensure proper delivery of medication, a newly opened and assembled bottle must be primed before you use it for the first time.

If your pharmacist assembled the unit for you, check to see if it has already been primed by pumping the unit once. If a full spray is emitted, the unit has already been primed. If no spray is emitted, you must prime the unit. Holding the bottle upright with your index and middle fingers on the two side arms of the pump, and your thumb on the bottom of the bottle, press the arms down fully until you see a full spray. Now the nasal spray is ready for use.

Do not re-prime the pump before each daily use because this will waste your medication.

Using the Medication

7. The recommended dose of Calcitonin-Salmon Nasal Spray is one spray once a day in one nostril.

Keep your head upright and carefully place the nozzle in one nostril.

Tilt the bottle until it is in a straight line with the nasal passage.

Firmly press down on the pump once to spray the medication into your nose. It is not necessary to inhale while this is being done. Please note: Because the mist is so fine, you may not feel it inside your nose. Also, some medication may drip out of your nose. However, in either case, the medication is absorbed. IMPORTANT: Do not "test" the spray unit or prime it before you use your daily dose because this will waste your medication.

Cleaning the Pump

Once or twice a week, wipe the nozzle with a clean, damp cloth. Dry the nozzle before replacing the dust cap

Storing the Unit

8. Holding the bottle with two fingers under the two side arms of the pump, gently replace the protective cap on the nasal spray unit. Be careful not to depress the pump while this is being done. Once the pump is primed, the unit must be kept at room temperature between 20 C to 25 C (68 F to 77 F) in the upright position until the medication is finished.

IMPORTANT

• Do not refrigerate the unit between doses
• Do not store the unit on its side

Bottles left at room temperature (opened or unopened) for more than 35 days must be discarded.

Refrigerated bottles are good until the expiration date stamped on the bottle and box.

Alternate Nostrils Daily

The first day, start with one spray in the left nostril. The next day, use one spray in the right nostril, and so on.

It is important to receive the correct daily amount of calcium and vitamin D, as directed by your healthcare provider.

IMPORTANT

• Use Calcitonin-Salmon Nasal Spray daily.

To ensure proper treatment, it is important to use your Calcitonin-Salmon Nasal Spray daily even if you have no symptoms of postmenopausal osteoporosis.

A single spray of Calcitonin-Salmon Nasal Spray, USP contains one daily dose, which is 200 I.U. of calcitonin-salmon. The fine mist is actually 0.09 mL (milliliter) of solution. Your bottle of Calcitonin-Salmon Nasal Spray contains at least 30 doses. Priming the pump as described in step 6 does not alter the total number of doses available in a bottle of Calcitonin-Salmon Nasal Spray. The bottle need only be primed once after assembly. Do not reprime or "test spray" your bottle before you use your daily dose of Calcitonin-Salmon Nasal Spray. This will waste your medication.

Please see your healthcare provider for complete product information for Calcitonin-Salmon Nasal Spray.

Distributed by:

Par Pharmaceutical Companies, Inc.

Spring Valley, NY 10977

Revised: 02/11 OS161-01-1-03

Additional barcode label applied by:
Physicians Total Care, Inc.
Tulsa, Oklahoma 74146

Principal Display Panel - Carton ⮝

Calcitonin Salmon Carton

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use CALCITONIN SALMON NASAL SPRAY safely and effectively. See full prescribing information for CALCITONIN SALMON NASAL SPRAY.

CALCITONIN SALMON nasal spray
Initial U.S. Approval: 1975

Dosage Forms And Strengths ⮝

Nasal Spray: 2200 USP Calcitonin Salmon Units per mL of calcitonin salmon in a 2 mL or 3.7 mL fill glass bottle with attached pump. Each actuation delivers 200 USP Calcitonin Salmon Units of calcitonin salmon (3)

Warnings And Precautions ⮝

• Serious hypersensitivity reactions including anaphylactic shock 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)
• Nasal adverse reactions, including severe ulceration can occur. Periodic nasal examinations are recommended (5.3)
• Malignancy: A meta-analysis of 21 clinical trials suggests an increased risk of overall malignancies in calcitonin salmon-treated patients (5.4, 6.1)
• Circulating antibodies to calcitonin salmon may develop, and may cause loss of response to treatment (5.5)

Drug Interactions ⮝

• 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)

Use In Specific Populations ⮝

• There are no data to support use in children (8.4)
  
• Nasal reactions are more common in elderly patients (8.5)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 11/2017

1 Indications And Usage ⮝

1.1 Treatment of Postmenopausal Osteoporosis

Calcitonin Salmon (synthetic origin) Nasal Spray is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause. Fracture reduction efficacy has not been demonstrated. Calcitonin Salmon (synthetic origin) Nasal Spray 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).

1.2 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.

2 Dosage And Administration ⮝

2.1 Basic Dosing Information

The recommended dose of calcitonin salmon nasal spray is 1 spray (200 USP Calcitonin Salmon Units) per day administered intranasally, alternating nostrils daily.

2.2 Priming (Activation) of Pump

Unopened calcitonin salmon nasal spray should be stored in the refrigerator. Before using the first dose of calcitonin salmon nasal spray, the patient should wait until it has reached room temperature. To prime the pump before it is used for the first time, the bottle should be held upright and the two white side arms of the pump depressed toward the bottle, repeat until a full spray is released. The pump is primed once the first full spray is emitted. To administer, the nozzle should first 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).

3 Dosage Forms And Strengths ⮝

Calcitonin Salmon (synthetic origin) Nasal Spray consists of one glass bottle with attached pump. The bottle contains 2 mL or 3.7 mL of calcitonin salmon clear solution at a concentration of 2200 USP Calcitonin Salmon Units per mL. A primed pump delivers 0.09 mL (200 USP Calcitonin Salmon Units) calcitonin salmon per actuation.

4 Contraindications ⮝

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)].

5 Warnings And Precautions ⮝

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions have been reported in patients receiving calcitonin salmon nasal spray, e.g., bronchospasm, swelling of the tongue or throat, anaphylaxis and anaphylactic shock. Reports of serious hypersensitivity reactions with injectable calcitonin salmon have 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.

6 Adverse 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)]
  
• Nasal Adverse Reactions [see Warnings and Precautions (5.3)]
  
• Malignancy [see Warnings and Precautions (5.4)]
  

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 nasal spray in the treatment of postmenopausal 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 Difference1 (%)	95% Confidence Interval2 (%)
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.

7 Drug Interactions ⮝

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

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

Calcitonin salmon nasal spray is not indicated for use in females of reproductive potential. There are no data with the use of calcitonin salmon nasal spray in pregnant women. In an animal reproduction study, subcutaneous administration of calcitonin-salmon to pregnant rabbits during organogenesis at 418 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).

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 (of 54 International Units/m2) and 70 to 278 times the 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.

10 Overdosage ⮝

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

Single doses of calcitonin salmon nasal spray up to 1600 International Units, doses up to 800 International Units per day for 3 days and chronic administration of doses up to 600 International Units per day have been studied without serious adverse effects.

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 (synthetic origin) Nasal Spray 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:

It is provided in a 2 mL or 3.7 mL fill glass bottle as a solution for nasal administration. This is sufficient medication for at least 14 doses (2 mL fill) or 30 doses (3.7 mL fill).

Active Ingredient: calcitonin salmon 2200 USP Calcitonin Salmon Units per mL (corresponding to 200 USP Calcitonin Salmon Units per 0.09 mL actuation).

Inactive Ingredients: benzalkonium chloride, hydrochloric acid (added as necessary to adjust pH), purified water and sodium chloride.

The activity of calcitonin salmon nasal spray 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 of 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

The information below, describing the clinical pharmacology of calcitonin, has been derived from studies with injectable calcitonin salmon. The mean bioavailability of calcitonin salmon nasal spray is approximately 3% of the injectable calcitonin salmon in healthy subjects and, therefore, the conclusions concerning the clinical pharmacology of this preparation may be different.

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 Tmax 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.

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 synthetic 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 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.

14 Clinical Studies ⮝

Two randomized, placebo-controlled, two-year trials were conducted in 266 postmenopausal women who were greater than 5 years postmenopause with spinal, forearm or femoral bone mineral density (BMD) at least one standard deviation below the normal value for healthy premenopausal women (T-score < -1). In both studies, a total of 144 patients received calcitonin salmon nasal spray 200 International Units or placebo daily. The intent-to-treat population comprised 139 patients who had at least one follow-up BMD measurement. In study 1, patients also received 500 mg daily calcium supplements, while in study 2, patients received no calcium supplementation. The primary endpoint for both studies was percent change in lumbar spine BMD at 2 years. Calcitonin salmon nasal spray increased lumbar vertebral BMD relative to placebo in women with low bone mass who were greater than 5 years post menopause (see Table 3 below).

Table 3: Calcitonin Salmon Nasal Spray: Lumbar Spine Bone 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.

16 How Supplied/storage And Handling ⮝

How Supplied
Calcitonin Salmon (synthetic origin) Nasal Spray is available as a metered dose clear solution in a 2 mL or 3.7 mL fill clear glass bottle that contains 2,200 USP Calcitonin Salmon Units calcitonin salmon per mL. A pump is attached to the bottle. After priming, the pump will deliver 200 USP Calcitonin Salmon Units per activation (0.09 mL per spray) (2 mL fill: NDC 60505-0823-0; 3.7 mL fill: NDC 60505-0823-6).

Storage and Handling
Store unopened bottle in refrigerator between 2 C to 8 C (36 F to 46 F). Protect from freezing.

Store bottle in use at room temperature between 20 C to 25 C (68 F to 77 F) in an upright position, for up to 30 days (2 mL fill) or 35 days (3.7 mL fill). Each bottle contains at least 14 doses (2 mL fill) or 30 doses (3.7 mL fill).

Discard bottle after 14 doses (2 mL fill) or 30 doses (3.7 mL fill).

Instructions For Use ⮝

Calcitonin Salmon (synthetic origin)

(kal" si toe' nin)

Nasal Spray

For Nasal Use Only.

Important information about your Calcitonin Salmon (synthetic origin) Nasal Spray:

• A single spray of Calcitonin Salmon (synthetic origin) Nasal Spray contains 1 daily dose of medicine.
• Each Calcitonin Salmon (synthetic origin) Nasal Spray bottle contains the right amount of medicine. The bottle may not be completely filled to the top. This is normal.
• This package contains 1 bottle of Calcitonin Salmon (synthetic origin) Nasal Spray with attached pump.
• 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.
• After you open your bottle of Calcitonin Salmon (synthetic origin) Nasal Spray, store it at room temperature between 20 C to 25 C (68 F to 77 F) in an upright position. Do not shake the bottle.

Preparing your Calcitonin Salmon (synthetic origin) Nasal Spray:
Step 1. Remove the bottle from your refrigerator and let it reach room temperature. Check the medicine in the bottle to make sure it is clear and colorless without particles.
Step 2. Remove the clear plastic dust cap and the blue safety clip from the nasal spray pump. See Figure 1. The safety clip prevents the accidental discharge of the spray in your pocket or purse.
Step 3. Check to see if your Calcitonin Salmon (synthetic origin) Nasal Spray has been primed. To make sure you get the right dose of Calcitonin Salmon (synthetic origin) Nasal Spray medicine you must prime each new bottle and pump before you use it for the first time. Check to see if the bottle and pump has already been primed by pressing on the pump 1 time. See Figure 2. If you see a full spray from the pump, the bottle and pump has already been primed for you. If you do not see a full spray, you must prime the bottle and pump.
Step 4. Priming your Calcitonin Salmon (synthetic origin) Nasal Spray: Hold the bottle upright with your pointer finger and middle finger on the 2 side arms of the pump, and your thumb on the bottom of the bottle. Firmly press down on the arms of the pump and press down again if needed until you see a full spray of medicine. See Figure 2. Now your Calcitonin Salmon (synthetic origin) Nasal Spray is ready for you to use. Do not prime the pump before you use it each day because this will waste your medicine.
Giving your Calcitonin Salmon (synthetic origin) Nasal Spray dose:
Step 5. Insert the nasal spray pump in 1 side of your nose. See Figure 3. Keep your head upright. Carefully tilt the bottle and place the nose spray pump into 1 side of your nose.
Step 6. Firmly press down on the nose spray pump to release the medicine. See Figure 4. Give 1 spray of Calcitonin Salmon (synthetic origin) Nasal Spray, 1 time daily, in 1 side of your nose (nostril). Spray your medicine in a different side of your nose each day. You do not need to breathe or inhale while you are giving your dose. You may not feel the spray inside your nose. Some of the medicine may drip out of your nose. This is normal, and you are still getting all of the medicine you need.
Cleaning your Calcitonin Salmon (synthetic origin) Nasal Spray pump:
Step 7. Wipe the nose spray pump with a clean, damp cloth 1 to 2 times a week. See Figure 5. Dry the nose spray pump with a clean cloth.
Storing your Calcitonin Salmon (synthetic origin) Nasal Spray:
Step 8. Replace the blue safety clip, then replace the protective cap on the nasal spray unit. See Figure 6. Be careful not to push down on the pump while you are putting the cap back on it. Do not refrigerate Calcitonin Salmon (synthetic origin) Nasal Spray between doses. Store Calcitonin Salmon (synthetic origin) Nasal Spray upright. Do not shake the bottle.

When should I throw away Calcitonin Salmon (synthetic origin) Nasal Spray?

• Unopened, refrigerated bottles can be used until the expiration date stamped on the bottle and box.
• Throw away Calcitonin Salmon (synthetic origin) Nasal Spray after you use 14 doses (2 mL fill) or 30 doses (3.7 mL fill) (sprays).
• Throw away Calcitonin Salmon (synthetic origin) Nasal Spray bottles left at room temperature (opened or unopened) for more than 30 days (2 mL fill) or 35 days (3.7 mL fill).

For more information on Calcitonin Salmon (synthetic origin) Nasal Spray, call Apotex Corp. at 1-800-706-5575.

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

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

Principal Display Panel ⮝

PRINCIPAL DISPLAY PANEL - PACKAGE CARTON LABEL

APOTEX CORP. NDC 60505-0823-6

Calcitonin Salmon (synthetic origin) Nasal Spray

(Calcitonin Salmon Nasal Solution, USP)

Rx

30 Doses per bottle

2200 USP Calcitonin Salmon Units/mL (200 USP Calcitonin Salmon Units/spray)

FOR INTRANASAL USE ONLY

REFRIGERATE UNTIL OPENED

CALCITONIN SALMON calcitonin salmon spray, metered

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60505-0823 Route of Administration NASAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CALCITONIN SALMON (UNII: 7SFC6U2VI5) (CALCITONIN SALMON - UNII:7SFC6U2VI5) CALCITONIN SALMON 200 [iU]

Inactive Ingredients Ingredient Name Strength BENZALKONIUM CHLORIDE (UNII: F5UM2KM3W7) HYDROCHLORIC ACID (UNII: QTT17582CB) WATER (UNII: 059QF0KO0R) SODIUM CHLORIDE (UNII: 451W47IQ8X)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60505-0823-0 1 in 1 CARTON 12/09/2008 1 14 in 1 BOTTLE, GLASS; Type 0: Not a Combination Product 2 NDC:60505-0823-6 1 in 1 CARTON 12/09/2008 2 30 in 1 BOTTLE, GLASS; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076396 12/09/2008

Labeler - Apotex Corp. (845263701)

Registrant - Apotex Inc. (209429182)

Establishment
Name	Address	ID/FEI	Business Operations
Richmond Hill		255092496	analysis(60505-0823) , manufacture(60505-0823)

Revised: 11/2017 Document Id: 78afdd54-08c7-93f8-113b-9eb08a7b603c 34391-3 Set id: c82eb602-12e1-692b-d660-f8d5b5736b54 Version: 8 Effective Time: 20171121 Apotex Corp.

Recent Major Changes ⮝

Indications and Usage (1.2) 3/2014

Warnings and Precautions (5.4) 3/2014

Information For The Patient ⮝

Read this Patient Information before you start using Calcitonin Salmon Nasal Solution and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is Calcitonin Salmon Nasal Solution?

Calcitonin Salmon Nasal Solution is a prescription medicine used to treat osteoporosis in women more than 5 years after menopause. Calcitonin Salmon Nasal Solution should be used for women who cannot use other treatments or who choose not to use other treatments for osteoporosis.

It is not known if Calcitonin Salmon Nasal Solution lowers the chance of having bone fractures.

Calcitonin Salmon Nasal Solution has not been shown to be effective in women less than 5 years after menopause.

It is not known if Calcitonin Salmon Nasal Solution is safe and effective in children under 18 years of age.

Who should not use Calcitonin Salmon Nasal Solution?

Do not use Calcitonin Salmon Nasal Solution if you:

• are allergic to calcitonin-salmon or any of the ingredients in Calcitonin Salmon Nasal Solution. See the end of this leaflet for a complete list of ingredients in Calcitonin Salmon Nasal Solution.

What should I tell my healthcare provider before using Calcitonin Salmon Nasal Solution? Before you use Calcitonin Salmon Nasal Solution, 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 Nasal Solution can harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if Calcitonin Salmon Nasal Solution passes into your breast milk. You and your healthcare provider should decide if you will use Calcitonin Salmon Nasal Solution 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 Nasal Solution.

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 Nasal Solution?

• For detailed instructions, see the Instructions for Use at the end of this Patient Information leaflet.
• Use Calcitonin Salmon Nasal Solution exactly as your healthcare provider tells you to use it.
• Do not use Calcitonin Salmon Nasal Solution until your healthcare provider shows you and you understand how to use it correctly.
• Use 1 spray of Calcitonin Salmon Nasal Solution, 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 Nasal Solution 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 Nasal Solution.
• Your healthcare provider should prescribe calcium and vitamin D to help prevent low calcium levels in your blood while you use Calcitonin Salmon Nasal Solution.
• Take your calcium and vitamin D as your healthcare provider tells you to.
• There are 30 doses (sprays) of Calcitonin Salmon Nasal Solution in each bottle. After 30 doses, 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 Nasal Solution, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of Calcitonin Salmon Nasal Solution?

Calcitonin Salmon Nasal Solution may cause serious side effects, including:

• allergic reactions

Some people have had an allergic reaction when using Calcitonin Salmon Nasal Solution. 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 Nasal Solution.

• low calcium levels in your blood (hypocalcemia)

Calcitonin Salmon Nasal Solution may lower the calcium levels in your blood. If you have low blood calcium before you start using Calcitonin Salmon Nasal Solution, it may get worse during treatment. Your low blood calcium must be treated before you use Calcitonin Salmon Nasal Solution. 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 Nasal Solution
• prescribe calcium and vitamin D to help prevent low calcium levels in your blood while you use Calcitonin Salmon Nasal Solution

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 Nasal Solution, 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 Nasal Solution until your nose irritation symptoms go away.

• risk of cancer

People who use calcitonin-salmon, the medicine in Calcitonin Salmon Nasal Solution, 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 Nasal Solution.

The most common side effects of Calcitonin Salmon Nasal Solution include:

• back pain
• muscle aches
• headache
• runny nose

These are not all the possible side effects of Calcitonin Salmon Nasal Solution. 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 Nasal Solution?

• Store open bottles of Calcitonin Salmon Nasal Solution at room temperature between 20 C to 25 C (68 F to 77 F) for 35 days.
• Store unopened bottles of Calcitonin Salmon Nasal Solution in the refrigerator between 2 C to 8 C (36 F to 46 F). Do not freeze.
• Store Calcitonin Salmon Nasal Solution bottles in an upright position.
• Safely throw away Calcitonin Salmon Nasal Solution in the trash after you have used 30 doses (sprays).

Keep Calcitonin Salmon Nasal Solution and all other medicines out of the reach of children.

General information about the safe and effective use of Calcitonin Salmon Nasal Solution.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Calcitonin Salmon Nasal Solution for a condition for which it was not prescribed. Do not give Calcitonin Salmon Nasal Solution 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 Nasal Solution. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Calcitonin Salmon Nasal Solution that is written for health professionals.

For more information, call 1-800-828-9393.

What are the ingredients in Calcitonin Salmon Nasal Solution?

Active Ingredients: calcitonin-salmon

Inactive Ingredients: sodium chloride, chlorobutanol (possesses a characteristic odor), hydrochloric acid (added as necessary to adjust pH), purified water and nitrogen.

Instructions for Use
Calcitonin (cal ci to nin) Salmon

Nasal Solution, USP

(Calcitonin Salmon Nasal Spray)

For Nasal Use Only.

Important information about your Calcitonin Salmon Nasal Solution:

• A single spray of Calcitonin Salmon Nasal Solution contains 1 daily dose of medicine.

• Each Calcitonin Salmon Nasal Solution bottle contains the right amount of medicine. The bottle may not be completely filled to the top. This is normal.

• This package contains 1 bottle of Calcitonin Salmon Nasal Solution and 1-screw-on pump.

• Store unopened bottles of Calcitonin Salmon Nasal Solution in the refrigerator between 36 F to 46 F (2 C to 8 C). Do not freeze.

• After you open your bottle of Calcitonin Salmon Nasal Solution, store it at room temperature between 20 C to 25 C (68 F to 77 F) in an upright position. Do not shake the bottle.

	Preparing your Calcitonin Salmon Nasal Solution: Step 1. Remove the bottle from your refrigerator and let it reach room temperature. Check the medicine in the bottle to make sure it is clear and colorless without particles. Important: If your Calcitonin Salmon Nasal Solution bottle and pump have already been put together by your pharmacist or healthcare provider, go to Step 6.
	Step 2. Keep the bottle upright and unscrew the white cap.
	Step 3. Remove the pump from the plastic protection bag.
	Step 4. Hold the bottle upright and insert the nose spray pump into the bottle. Turn the pump clockwise to tighten it until it is securely attached to the bottle. See Figure E. Do not push down on the pump when it is not attached to the bottle.
	Step 5. Holding the bottle upright with your index finger on top of one of the two side arms of the pump, gently remove the clear protective cap from the top of the nozzle. See Figure F.
	Step 6. Check to see if your Calcitonin Salmon Nasal Solution has been primed. To make sure you get the right dose of Calcitonin Salmon Nasal Solution medicine you must prime each new bottle and pump before you use it for the first time. If your pharmacist or healthcare provider puts the bottle and pump together for you, check to see if it has already been primed by pressing on the pump 1 time. See Figure G. If you see a full spray from the pump, the bottle and pump has already been primed for you. If you do not see a full spray, you must prime the bottle and pump.
	Priming your Calcitonin Salmon Nasal Solution: Step 7. Hold the bottle upright with your pointer finger and middle finger on the two side arms of the pump, and your thumb on the bottom of the bottle. Firmly press down on the arms of the pump and press down again if needed until you see a full spray of medicine. See Figure G. Now your Calcitonin Salmon Nasal Solution is ready for you to use. Do not prime the pump before you use it each day because this will waste your medicine.
	Giving your Calcitonin Salmon Nasal Solution dose: Step 8. Insert the nasal spray pump in 1 side of your nose.See Figure H. Keep your head upright. Carefully tilt the bottle and place the nose spray pump into 1 side of your nose.
	Step 9. Firmly press down on the nose spray pump to release the medicine. See Figure I. Give 1 spray of Calcitonin Salmon Nasal Solution, 1 time daily, in 1 side of your nose (nostril). Spray your medicine in a different side of your nose each day. You do not need to breathe in or inhale while you are giving your dose. You may not feel the spray inside your nose. Some of the medicine may drip out of your nose. This is normal, and you are still getting all of the medicine you need.
	Cleaning your Calcitonin Salmon Nasal Solution pump: Step 10. Wipe the nose spray pump with a clean, damp cloth 1 to 2 times a week. See Figure J. Dry the nose spray pump with a clean cloth.
	Storing your Calcitonin Salmon Nasal Solution: Step 11. Gently put the protective cap back on the nasal spray pump. Hold the bottle with 2 fingers under the two side arms of the pump. See Figure K. Be careful not push down on the pump while you are putting the cap back on it. Do not refrigerate Calcitonin Salmon Nasal Solution between doses. Store Calcitonin Salmon Nasal Solution upright. Do not shake the bottle.

When should I throw away Calcitonin Salmon Nasal Solution?

• Unopened, refrigerated bottles can be used until the expiration date stamped on the bottle and box.
• Throw away Calcitonin Salmon Nasal Solution after you use 30 doses (sprays).
• Throw away Calcitonin Salmon Nasal Solution bottles left at room temperature (opened or unopened) for more than 35 days.

For more information on Calcitonin Salmon Nasal Solution and how to put it together, call Par Pharmaceutical at 1-800-828-9393.

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Package/label Principal Display Panel ⮝

Calcitonin Salmon Label

CALCITONIN SALMON calcitonin salmon spray, metered

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:49884-161 Route of Administration NASAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CALCITONIN SALMON (UNII: 7SFC6U2VI5) (CALCITONIN SALMON - UNII:7SFC6U2VI5) CALCITONIN SALMON 200 [iU] in 0.09 mL

Inactive Ingredients Ingredient Name Strength HYDROCHLORIC ACID (UNII: QTT17582CB) NITROGEN (UNII: N762921K75) SODIUM CHLORIDE (UNII: 451W47IQ8X) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:49884-161-11 3.8 mL in 1 BOTTLE, GLASS; Type 0: Not a Combination Product 06/08/2009

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076979 06/08/2009

Labeler - Par Pharmaceutical, Inc. (092733690)

Revised: 3/2019 Document Id: dcd2ee6b-bb57-4f25-bdee-18b68fc91e78 34391-3 Set id: a6eaedb3-5c96-4859-be43-a48c9c818bc7 Version: 12 Effective Time: 20190329 Par Pharmaceutical, Inc.

1 Indications And Usage ⮝

1.1 Treatment of Postmenopausal Osteoporosis

Calcitonin-salmon nasal spray is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause. Fracture reduction efficacy has not been demonstrated. Calcitonin-salmon nasal spray 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).

1.2 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 nasal spray has not been shown to increase spinal bone mineral density in early postmenopausal women.

2 Dosage And Administration ⮝

2.1 Basic Dosing Information

The recommended dose of calcitonin-salmon nasal spray is 1 spray (200 International Units) per day administered intranasally, alternating nostrils daily.

2.2 Priming (Activation) of Pump

Unopened calcitonin-salmon nasal spray should be stored in the refrigerator. Before using the first dose of calcitonin-salmon nasal spray, the patient should wait until it has reached room temperature. To prime the pump before it is used for the first time, the bottle should be held upright and the two white side arms of the pump depressed toward the bottle, repeat until a full spray is released. The pump is primed once the first full spray is emitted. To administer, the nozzle should first 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).

3 Dosage Forms And Strengths ⮝

Calcitonin-salmon nasal spray consists of one glass bottle and one screw-on pump. The bottle contains 3.7 mL of calcitonin-salmon clear solution at a concentration of 2200 International Units per mL. A primed pump delivers 0.09 mL (200 International Units) calcitonin-salmon per actuation.

4 Contraindications ⮝

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)].

5 Warnings And Precautions ⮝

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions have been reported in patients receiving calcitonin-salmon nasal spray, e.g., bronchospasm, swelling of the tongue or throat, anaphylaxis and anaphylactic shock. Reports of serious hypersensitivity reactions with injectable calcitonin-salmon have 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 Medical Services Department of Novartis Pharmaceuticals Corporation.

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.

6 Adverse 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)]
  
• Nasal Adverse Reactions [see Warnings and Precautions (5.3)]
  
• Malignancy [see Warnings and Precautions (5.4)]
  

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 nasal spray in the treatment of postmenopausal osteoporosis was assessed in 5 randomized, double-blind, placebo controlled trials that enrolled postmenopausal women, aged 45 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% 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 Difference1 (%)	95% Confidence Interval2 (%)
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.

7 Drug Interactions ⮝

No formal drug interaction studies have been performed with calcitonin-salmon nasal spray.

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

Pregnancy Category C:

Risk Summary

There are no adequate and well-controlled studies in pregnant women. Calcitonin-salmon nasal spray should be used during pregnancy only if the potential benefit justifies the use as compared with potential risks to the patient and fetus. Based on animal data, calcitonin-salmon nasal spray is predicted to have low probability of increasing the risk of adverse developmental outcomes above background risk.

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 18 times the parenteral dose (of 54 International Units/m2) and 70 278 times the 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.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. No studies have been conducted to assess the impact of calcitonin-salmon nasal spray on milk production in humans, its presence in human breast milk, or its effects on the breastfed child. Because many drugs are excreted in human milk, caution should be exercised when calcitonin-salmon nasal spray is administered to a nursing woman. 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 multicentered, 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.

10 Overdosage ⮝

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

Single doses of calcitonin-salmon nasal spray up to 1600 International Units, doses up to 800 International Units per day for 3 days and chronic administration of doses up to 600 International Units per day have been studied without serious adverse effects.

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 nasal spray 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:

It is provided in a 3.7 mL fill glass bottle as a solution for nasal administration. This is sufficient medication for 30 doses.

Active Ingredient: calcitonin-salmon 2200 International Units per mL (corresponding to 200 International Units per 0.09 mL actuation).

Inactive Ingredients: sodium chloride, benzalkonium chloride, hydrochloric acid (added as necessary to adjust pH) and purified water.

The activity of calcitonin-salmon nasal spray 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 of 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

The information below, describing the clinical pharmacology of calcitonin, has been derived from studies with injectable calcitonin-salmon. The mean bioavailability of calcitonin-salmon nasal spray is approximately 3% of the injectable calcitonin-salmon in healthy subjects and, therefore, the conclusions concerning the clinical pharmacology of this preparation may be different.

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 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 Tmax 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.

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 synthetic 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 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.

14 Clinical Studies ⮝

Two randomized, placebo-controlled, two-year trials were conducted in 266 postmenopausal women who were greater than 5 years postmenopause with spinal, forearm or femoral bone mineral density (BMD) at least one standard deviation below the normal value for healthy premenopausal women (T-score < -1). In both studies, a total of 144 patients received calcitonin-salmon nasal spray 200 International Units or placebo daily. The intent-to-treat population comprised 139 patients who had at least one follow-up BMD measurement. In study 1, patients also received 500 mg daily calcium supplements, while in study 2, patients received no calcium supplementation. The primary endpoint for both studies was percent change in lumbar spine BMD at 2 years. Calcitonin-salmon nasal spray increased lumbar vertebral BMD relative to placebo in women with low bone mass who were greater than 5 years post menopause (see Table 3 below).

Table 3: Calcitonin-Salmon Nasal Spray: Lumbar Spine Bone 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.

16 How Supplied/storage And Handling ⮝

How Supplied

Calcitonin-Salmon Nasal Spray is available as a metered dose clear solution in a 3.7 mL fill clear glass bottle that contains 2200 International Units calcitonin-salmon per mL. A screw-on pump is provided. After priming, the pump will deliver 200 International Units per activation (0.09 mL per spray)................................................................. NDC 0781-6320-79

Storage and Handling

Store unopened bottle in refrigerator between 2 C 8 C (36 F 46 F). Protect from freezing.

Store bottle in use at room temperature between 15 C 30 C (59 F 86 F) in an upright position, for up to 35 days. Each bottle contains at least 30 doses.

Discard bottle after 30 doses.

No Title 1572457517 ⮝

Patient Information

Calcitonin-Salmon

Nasal Spray

Read this Patient Information before you start using calcitonin-salmon nasal spray and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is calcitonin-salmon?

Calcitonin-salmon is a prescription medicine used to treat osteoporosis in women more than 5 years after menopause. Calcitonin-salmon should be used for women who cannot use other treatments or who choose not to use other treatments for osteoporosis.

It is not known if calcitonin-salmon lowers the chance of having bone fractures.

Calcitonin-salmon has not been shown to be effective in women less than 5 years after menopause.

It is not known if calcitonin-salmon is safe and effective in children under 18 years of age.

Who should not use calcitonin-salmon?

Do not use calcitonin-salmon if you:

• are allergic to calcitonin-salmon or any of the ingredients in calcitonin-salmon nasal spray. See the end of this leaflet for a complete list of ingredients in calcitonin-salmon.

What should I tell my healthcare provider before using calcitonin-salmon?

Before you use calcitonin-salmon, 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 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 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.

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?

• For detailed instructions, see the Instructions for Use at the end of this Patient Information leaflet.
• Use calcitonin-salmon exactly as your healthcare provider tells you to use it.
• Do not use calcitonin-salmon until your healthcare provider shows you and you understand how to use it correctly.
• Use 1 spray of calcitonin-salmon, 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 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.
• Your health care provider should prescribe calcium and vitamin D to help prevent low calcium levels in your blood while you use calcitonin-salmon.
• Take your calcium and vitamin D as your healthcare provider tells you to.
• There are 30 doses (sprays) of calcitonin-salmon in each bottle. After 30 doses, 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, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of calcitonin-salmon?

Calcitonin-salmon may cause serious side effects, including:

• allergic reactions
  Some people have had an allergic reaction when using calcitonin-salmon. 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.
• low calcium levels in your blood (hypocalcemia)
  Calcitonin-salmon may lower the calcium levels in your blood. If you have low blood calcium before you start using calcitonin-salmon, it may get worse during treatment. Your low blood calcium must be treated before you use calcitonin-salmon. 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
  • prescribe calcium and vitamin D to help prevent low calcium levels in your blood while you use calcitonin-salmon.

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, 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 until your nose irritation symptoms go away.
• risk of cancer
  People who use calcitonin-salmon, the medicine in calcitonin-salmon 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.

The most common side effects of calcitonin-salmon include:

• back pain
• muscle aches
• headache
• runny nose

These are not all the possible side effects of calcitonin-salmon. 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?

• Store open bottles of calcitonin-salmon at room temperature between 59 F to 86 F (15 C to 30 C) for 35 days.
• Store unopened bottles of calcitonin-salmon in the refrigerator between 36 F to 46 F (2 C to 8 C). Do not freeze.
• Store calcitonin-salmon bottles in an upright position.
• Safely throw away calcitonin-salmon in the trash after you have used 30 doses (sprays).

Keep calcitonin-salmon and all other medicines out of the reach of children.

General information about the safe and effective use of calcitonin-salmon.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use calcitonin-salmon for a condition for which it was not prescribed. Do not give calcitonin-salmon 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. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about calcitonin-salmon that is written for health professionals.

For more information, call 1-800-525-8747.

What are the ingredients in calcitonin-salmon?

Active Ingredients: calcitonin-salmon

Inactive Ingredients: sodium chloride, benzalkonium chloride, hydrochloric acid and purified water.