1. What Is Fortical Nasal Spray?
2. Do Not Use Fortical Nasal Spray If You:
3. Before You Use Fortical Nasal Spray, Tell Your Healthcare Provider If You:
4. Especially Tell Your Healthcare Provider If You Take:
5. How Should I Use Fortical Nasal Spray?
6. Fortical Nasal Spray May Cause Serious Side Effects, Including:
7. Irritation Of Your Nose Can Happen While You Are Using Fortical Nasal Spray, Especially If You Are Over 65 Years Of Age. Call Your Healthcare Provider Right Away If You Have Any Of These Symptoms Of Nose Irritation:
8. What Are The Ingredients In Fortical Nasal Spray?
9. Important Information About Your Fortical Nasal Spray:
10. Patient Information

What Is Fortical Nasal Spray? ⮝

Fortical Nasal Spray is a prescription medicine used to treat osteoporosis in women more than 5 years after menopause. Fortical 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 Fortical Nasal Spray lowers the chance of having bone fractures.

Calcitonin-salmon the active ingredient in Fortical Nasal Spray has not been shown to be effective in women less than 5 years after menopause.

It is not known if Fortical Nasal Spray is safe and effective in children under 18 years of age.

Do Not Use Fortical Nasal Spray If You: ⮝

• are allergic to calcitonin-salmon or any of the ingredients in Fortical Nasal Spray.

Before You Use Fortical 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 Fortical Nasal Spray can harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if Fortical Nasal Spray passes into your breast milk. You and your healthcare provider should decide if you will use Fortical 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 Fortical 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 Fortical Nasal Spray? ⮝

• For detailed instructions,

Fortical Nasal Spray May Cause Serious Side Effects, Including: ⮝

• allergic reactions.Some people have had an allergic reaction when using Fortical 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 Fortical Nasal Spray.

• low calcium levels in your blood (hypocalcemia).Fortical Nasal Spray may lower the calcium in your blood. If you have low blood calcium before you start using Fortical Nasal Spray, it may get worse during treatment. Your low blood calcium must be treated before you use Fortical 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 Fortical Nasal Spray
  • prescribe calcium and vitamin D to help prevent low calcium levels in your blood while you use Fortical 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 Fortical Nasal Spray, Especially If You Are Over 65 Years Of Age. Call Your Healthcare Provider Right Away 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 Fortical Nasal Spray until your nose irritation symptoms go away.

• risk of cancer

People who use calcitonin-salmon, the medicine in Fortical Nasal Spray, may have an increased risk of cancer. Your healthcare provider should check while you are using Fortical to

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

Keep Fortical Nasal Spray and all other medicines out of the reach of children.

General Information about the safe and effective use of Fortical Nasal Spray.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Fortical Nasal Spray for a condition for which it was not prescribed. Do not give Fortical Nasal Spray to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information Leaflet summarizes the most important information about Fortical Nasal Spray. If you would like more information about Fortical Nasal Spray talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Fortical Nasal Spray that is written for health professionals.

For more information, go to www.upsher-smith.com or call 1-888-650-3789.

What Are The Ingredients In Fortical Nasal Spray? ⮝

Active Ingredient: calcitonin-salmon

Inactive Ingredients: sodium chloride, citric acid, phenylethyl alcohol, benzyl alcohol, polysorbate 80, hydrochloric acid or sodium hydroxide and purified water.

Instructions for Use
Fortical[f r-t -k l]
(calcitonin-salmon[rDNA origin])
Nasal Spray

For Nasal Use Only

Important Information About Your Fortical Nasal Spray: ⮝

• A single spray of Fortical Nasal Spray contains 1 daily dose of medicine.
• Each Fortical 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 Fortical Nasal Spray and 1 screw-on pump.

• Store unopened bottles of Fortical Nasal Spray in the refrigerator between 36 F to 46 F (2 C to 8 C). Do not freeze.
• After you open your bottle of Fortical Nasal Spray, store it at room temperature between 68 F to 77 F (20 C to 25 C) in an upright position. Do not shake the bottle.

Preparing your Fortical Nasal Spray

Remove the bottle from your refrigerator and let it reach room temperature.

	Step 1.Opening the Bottle.Set bottle on a flat surface like a table or counter top. Hold the bottle firmly while unscrewing the cap to avoid spilling any Fortical Nasal Spray. Important: If your pharmacist attached the pump for you, skip to Step 4.
	Step 2.Unwrapping the Pump.Carefully cut the wrapper with scissors or knife, and tear away from the pump. Be careful not to cut, bend, or touch the feed tube at the bottom.
	Step 3. Attaching the Pump.Hold the bottle on a flat surface (like a table), and screw the pump onto bottle by gripping the grooves of the pump and twisting clockwise until the pump is tightly sealed to the bottle.
	Step 4. Removing Cap.To remove the cap from the pump, twist slightly while pulling up. Save the cap to replace after each use.
Save the lock tab, and push it back onto the pump after each use to avoid accidentally wasting any Fortical Nasal Spray	Step 5. Removing the Lock Tab.Grasp the lock tab between the thumb and forefinger, while holding the bottle on a flat surface. Pull sideways to remove the tab and unlock the pump.
	Step 6. Prime New Pump Before First Use. Before you use a new bottle of Fortical Nasal Spray for the first time, you will need to prime it. This will make sure you get the right dose of medicine each time you use it. After you attach the pump to the bottle, and the pump and bottle have reached room temperature, you should: Hold the bottle upright. With your index and middle fingers on each side of the top of the pump, and with your thumb under the bottle, push the pump down. Push the pump down at least 5 times, until you Unopened, refrigerated bottles can be used until the expiration date stamped on the bottle and box. Throw away Fortical Nasal Spray after you use 30 doses (sprays). This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by UPSHER-SMITH LABORATORIES, INC. Maple Grove, MN USA 55369 www.upsher-smith.com Revised 0714

Patient Information ⮝

See FDA-approved patient labeling (Patient InformationandInstructions for Use).

• Instruct patients on pump assembly, priming of the pump, and nasal introduction of Fortical nasal spray. Although instructions for patients are supplied with the individual bottle, procedures for use should be demonstrated to each patient [seeDosage and Administration (2.2)]. Patients should notify their healthcare provider if they develop significant nasal irritation [seeWarnings and Precautions (5.3)].
• Inform patients of the potential increase in risk of malignancy [seeWarnings 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 [seeDosage 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 [seeHow Supplied/Storage and Handling (16)]. Advise patients that the bottle should be discarded after 30 doses, because after 30 doses, each spray may not deliver the correct amount of medication even if the bottle is not completely empty.

Distributed by
UPSHER-SMITH LABORATORIES, INC.
Maple Grove, MN USA 55369

US Patent RE 40,182
US Patent RE 43,580
US Patent 6,440,392

Revised 0714

1. No Title 1572550326
2. No Title 1572450678
3. Description
4. Clinical Pharmacology
5. Indications And Usage
6. Contraindications
7. Warnings
8. Precautions
9. Adverse Reactions
10. Overdosage
11. Dosage And Administration
12. How Supplied
13. Fortical Calcitonin-salmon (rdna Origin)nasal Spray
14. Principal Display Panel - 2200 Iu/ml Carton
15. Highlights Of Prescribing Information
16. Recent Major Changes
17. Dosage Forms And Strengths
18. Warnings And Precautions
19. Drug Interactions
20. Use In Specific Populations
21. 1 Indications And Usage
22. 2 Dosage And Administration
23. 3 Dosage Forms And Strengths
24. 4 Contraindications
25. 5 Warnings And Precautions
26. 6 Adverse Reactions
27. 7 Drug Interactions
28. 8 Use In Specific Populations
29. 10 Overdosage
30. 11 Description
31. 12 Clinical Pharmacology
32. 13 Nonclinical Toxicology
33. 14 Clinical Studies
34. 16 How Supplied/storage And Handling
35. Principal Display Panel - 3.7 Ml Bottle Carton

No Title 1572550326 ⮝

Distributed by

UPSHER-SMITH LABORATORIES, INC.
Minneapolis, MN USA 55447-4709

US Patent RE 40,182
US Patent 6,103,495
US Patent 6,210,925
US Patent 6,627,438
US Patent 6,737,250
US Patent 5,789,234

104043-01
Revised 0110

Relabeling of "ADDITIONAL" Barcode Label by:
Physicians Total Care, Inc.
Tulsa, OK 74146

No Title 1572450678 ⮝

For Intranasal Use Only

Rx only

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.

The active ingredient in FORTICAL calcitonin-salmon (rDNA origin) Nasal Spray is a polypeptide of 32 amino acids manufactured by recombinant DNA technology and is identical to calcitonin-salmon produced by chemical synthesis.

This is shown by the following graphic formula:

It is provided in a 3.7 mL fill glass bottle as a solution for intranasal administration with sufficient medication for at least 30 doses. Each spray delivers 200 International Units calcitonin-salmon in a volume of 0.09 mL.

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

Inactive Ingredients: Sodium Chloride USP, Citric Acid USP, Phenylethyl Alcohol USP, Benzyl Alcohol NF, Polysorbate 80 NF, Hydrochloric Acid NF or Sodium Hydroxide NF (added as necessary to adjust pH) and Purified Water USP.

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 the 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 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 the 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 women. 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' fracture). Vertebral fractures occur with the highest frequency and are associated with back pain, spinal deformity and a loss of height.

Calcitonin, given by the intranasal route, has been shown to increase spinal bone mass in postmenopausal 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 International Units 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 International Units 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 women.

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 conducted with FORTICAL calcitonin-salmon (rDNA origin) Nasal Spray.

Gastrointestinal Tract

Some evidence from studies with injectable preparations suggests 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 FORTICAL calcitonin-salmon (rDNA origin) Nasal Spray.

Pharmacokinetics and Drug Metabolism

The pharmacokinetic properties of FORTICAL calcitonin-salmon (rDNA origin) Nasal Spray after multiple dose administration were shown to be similar to that of a commercially available calcitonin-salmon product in healthy volunteers. 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, Fortical activity should be evaluated by using clinical parameters of efficacy.

Indications And Usage ⮝

Postmenopausal Osteoporosis

FORTICAL calcitonin-salmon (rDNA origin) Nasal Spray is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause with low bone mass relative to healthy premenopausal women. Use of FORTICAL calcitonin-salmon (rDNA origin) Nasal Spray is recommended in conjunction with an adequate calcium (at least 1000 mg elemental calcium per day) and Vitamin D (400 International Units per day) intake to retard the progressive loss of bone mass. The evidence of efficacy for calcitonin-salmon is based on increases in spinal bone mineral density (BMD) observed in clinical trials.

Two randomized, placebo-controlled trials were conducted in 325 postmenopausal women (227 treated with calcitonin-salmon nasal spray and 98 treated with placebo) with spinal, forearm or femoral BMD at least one standard deviation below the normal value for healthy premenopausal women. These studies conducted over two years demonstrated that 200 International Units daily of calcitonin-salmon nasal spray increases lumbar vertebral BMD relative to baseline and relative to placebo in osteoporotic women who were greater than 5 years postmenopause. Calcitonin-salmon nasal spray produced statistically significant increases in lumbar vertebral BMD compared to placebo as early as 6 months after initiation of therapy with persistence of this level for up to 2 years of observation.

No effects of calcitonin-salmon nasal spray on cortical bone of the forearm or hip were demonstrated. However, in one study, BMD of the hip showed a statistically significant increase compared with placebo in a region composed of predominantly trabecular bone after 1 year of treatment changing to a trend at 2 years that was no longer statistically significant.

Contraindications ⮝

Clinical allergy to calcitonin-salmon.

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 emergency treatment if such a reaction should 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 a calcitonin-salmon injectable product. Physicians may wish to refer patients who require skin testing to an allergist. A detailed skin testing protocol is available from Upsher-Smith Laboratories, Inc. by calling toll-free at 1-800-654-2299.

Precautions ⮝

1. Drug Interactions

Formal studies designed to evaluate drug interactions with calcitonin-salmon have not been done.

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.

2. 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 have been reported in up to 9% of patients who received a calcitonin-salmon nasal spray and in up to 12% of patients who received placebo nasal spray in studies in postmenopausal women. 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 a 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 a calcitonin-salmon nasal spray who was receiving 400 International Units 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.

3. Information for Patients

Careful instructions on pump assembly, priming of the pump and nasal introduction of FORTICAL calcitonin-salmon (rDNA origin) Nasal Spray should be given to the patient. Although instructions for patients are supplied with the individual bottle, procedures for use should be demonstrated to each patient. Patients should notify their physician if they develop significant nasal irritation.

Get emergency medical help right away if you have any of the following symptoms of a serious allergic reaction:

• trouble breathing
• swelling of your face, throat or tongue
• rapid heartbeat
• chest pain
• feel faint or dizzy

Patients should be advised of the following:

• Store new, unassembled bottles in the refrigerator between 36-46 F (2-8 C).
• Protect the product from freezing.
• Keep the bottle of Fortical Nasal Spray away from light.
• Before priming the pump and using a new bottle, allow it to reach room temperature.
• After opening a new bottle of Fortical Nasal Spray, store bottle in use with pump attached at room temperature, 68 F to 77 F (20 C to 25 C), in an upright position. Each bottle contains enough medicine for 30 doses.
• Throw away the empty bottle of Fortical Nasal Spray after you have used 30 doses.
• See DOSAGE AND ADMINISTRATION, Priming (Activation) of Pump for complete instructions on priming the pump and administering FORTICAL calcitonin-salmon (rDNA origin) Nasal Spray.

4. Carcinogenicity, Mutagenicity, Impairment of Fertility

An increased incidence of non-functioning pituitary adenomas has been observed in 1-year toxicity studies in Sprague-Dawley and Fischer 344 Rats administered (subcutaneously) calcitonin-salmon at dosages of 80 International Units 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 the 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 four strains of Salmonella typhimurium and two strains of Escherichia coli, 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 Chinese Hamster ovary cells in vitro.

5. 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.

6. 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. FORTICAL calcitonin-salmon (rDNA origin) Nasal Spray is not indicated for use in pregnancy.

7. 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.

8. Pediatric Use

There are no data to support the use of FORTICAL calcitonin-salmon (rDNA origin) 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 limited.

9. Geriatric Use

In a 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 ⮝

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. Most adverse reactions were mild to moderate in severity. Nasal adverse events were most common with 70% mild, 25% moderate, and 5% severe in nature (placebo rates were 71% mild, 27% moderate, and 2% severe).

Adverse Reactions Occurring in at Least 3% of Postmenopausal Patients Treated Chronically

Adverse Reaction	Calcitonin-Salmon Nasal Spray N=341 % of Patients	Placebo N=131 % of Patients
* 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.
Rhinitis	12.0	6.9
Symptom of Nose*	10.6	16.0
Back Pain	5.0	2.3
Arthralgia	3.8	5.3
Epistaxis	3.5	4.6
Headache	3.2	4.6

In addition, the following adverse events were reported in fewer than 3% of patients during chronic therapy with calcitonin-salmon nasal spray. Adverse events reported in 1%-3% of patients are identified with an asterisk(*). The remainder occurred in less than 1% of patients. 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.

Body as a whole General Disorders: influenza-like symptoms*, fatigue*, edema (facial, peripheral, and generalized), fever

Integumentary: erythematous rash*, skin ulceration, eczema, alopecia, pruritus, increased sweating

Musculoskeletal/Collagen: arthrosis*, myalgia*, arthritis, polymyalgia rheumatica, stiffness

Respiratory/Special Senses: sinusitis*, upper respiratory tract infection*, bronchospasm*, pharyngitis, bronchitis, pneumonia, coughing, dyspnea, taste perversion, parosmia, nasal congestion, sneezing, allergic rhinitis, nasal odor, mucosal excoriation, rhinitis ulcerative

Cardiovascular: hypertension*, angina pectoris*, tachycardia, palpitation, bundle branch block, myocardial infarction

Gastrointestinal: dyspepsia*, constipation*, abdominal pain*, nausea*, diarrhea*, vomiting, flatulence, increased appetite, gastritis, dry mouth

Liver/Metabolic: cholelithiasis, hepatitis, thirst, weight increase

Endocrine: goiter, hyperthyroidism

Urinary System: cystitis*, pyelonephritis, hematuria, renal calculus

Central and Peripheral Nervous System: dizziness*, paresthesia*, vertigo, migraine, neuralgia, agitation

Hearing/Vestibular: tinnitus, hearing loss, earache

Vision: abnormal lacrimation*, conjunctivitis*, blurred vision, vitreous floater, visual disturbance

Vascular: flushing, cerebrovascular accident, thrombophlebitis

Hematologic/Resistance Mechanisms: lymphadenopathy*, infection*, anemia

Psychiatric: depression*, insomnia, anxiety, anorexia

Immune System Disorders: hypersensitivity, anaphylaxis and anaphylactic shock

Common adverse reactions associated with the use of injectable calcitonin-salmon occurred less frequently in patients treated with calcitonin-salmon nasal spray than in those patients treated with injectable calcitonin. Nausea, with or without vomiting, which occurred in 1.8% of patients treated with the nasal spray (and 1.5% of those receiving placebo nasal spray) occurs in about 10% of patients who take injectable calcitonin-salmon. Flushing, which occurred in less than 1% of patients treated with the nasal spray, occurs in 2-5% of patients treated with injectable calcitonin-salmon. Although the administered dosages of injectable and nasal spray calcitonin-salmon are comparable (50-100 units daily of injectable versus 200 units daily of nasal spray), the nasal dosage form has a mean bioavailability of about 3% (range 0.3%-30.6%) and therefore provides less drug to the systemic circulation, possibly accounting for the decrease in frequency of adverse reactions.

The collective foreign marketing experience with calcitonin-salmon nasal spray does not show evidence of any notable difference in the incidence profile of reported adverse reactions when compared with that seen in the clinical trials.

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 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. A 1000 International Units dose of calcitonin-salmon injectable product given subcutaneously may produce nausea and vomiting. A 32 International Units per kg per day dose of calcitonin-salmon injectable product for 1or 2 days demonstrated no additional adverse effects.

There have been no reports of hypocalcemic tetany. However, the pharmacologic actions of FORTICAL calcitonin-salmon (rDNA origin) 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 ⮝

The recommended dose of FORTICAL calcitonin-salmon (rDNA origin) Nasal Spray in postmenopausal osteoporotic patients is 1 spray (200 International Units) per day administered intranasally, alternating nostrils daily. Each bottle, filled with 3.7 mL of solution, contains enough medication for 30 doses. Drug effect may be monitored by periodic measurements of lumbar vertebral bone mass to document stabilization of bone loss or increases in bone density. Effects of calcitonin-salmon nasal spray on biochemical markers of bone turnover have not been consistently demonstrated in studies in postmenopausal osteoporosis. Therefore, these parameters should not be solely utilized to determine clinical response to calcitonin-salmon nasal spray therapy in these patients.

Priming (Activation) of Pump

Before the first dose and administration, allow the bottle to reach room temperature. Remove the protective cap and clip from the bottle of FORTICAL calcitonin-salmon (rDNA origin) Nasal Spray. To prime the pump, hold the bottle upright and depress the two white side arms of the pump toward the bottle at least 5 times until a full spray is produced. The pump is primed once the first full spray is emitted. To administer, the nozzle should be carefully placed into the nostril with the head in the upright position and the pump firmly depressed toward the bottle. The pump should NOT be primed before each daily use.

How Supplied ⮝

FORTICAL calcitonin-salmon (rDNA origin) Nasal Spray is presented as a metered dose solution in a 3.7 mL fill amber glass bottle. It is available in a dosage strength of 200 International Units per activation (0.09 mL). A screw-on pump is provided.

Following priming, the pump will deliver solution containing 200 International Units of calcitonin-salmon per activation. FORTICAL calcitonin-salmon (rDNA origin) Nasal Spray contains 2200 International Units/mL calcitonin-salmon and is provided in individual boxes containing one glass bottle with screw cap and one screw-on pump (NDC# 54868-5499-0).

Store and Dispense

Store unopened bottle in refrigerator between 36 F to 46 F (2 C to 8 C). Protect from freezing. After opening, store bottle in use in an upright position at 68 F to 77 F (20 C to 25 C). Excursions permitted to 15 C to 30 C (59 F to 86 F). Throw away the empty bottle of Fortical Nasal Spray after you have used 30 doses.

Fortical Calcitonin-salmon (rdna Origin)nasal Spray ⮝

Patient Information and Instructions for Use

Patient Information

Fortical [f r-t -k l]
calcitonin-salmon (rDNA origin)
Nasal Spray

Read the Patient Information that comes with Fortical Nasal Spray before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

What is Fortical Nasal Spray?

Fortical Nasal Spray is a prescription medicine used to treat osteoporosis in women, who went through menopause (postmenopausal women) at least 5 years ago.

Fortical Nasal Spray contains calcitonin salmon, a man-made protein that is similar to a protein occurring in the human body. When you spray Fortical 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 has been shown to slow down bone loss at the spine. Slowing down bone loss, while new bone building continues, helps to increase bone mass at the spine.

Fortical Nasal Spray is taken with calcium and vitamin D supplements recommended by your doctor, to help slow down further bone loss. If you are not getting enough calcium and vitamin D in your daily diet, your doctor may recommend a calcium or vitamin D supplement. The amount of calcium and vitamin D needed each day can vary from person to person. Most people generally require at least 1000 mg of calcium and 400 International Units of vitamin D each day. Vitamin D is necessary for your body to use calcium to build bone material. That is why your doctor may have recommended that you add a vitamin D supplement to your diet. It is important to take all the calcium and vitamin D supplements your doctor directs each day.

Who should not use Fortical Nasal Spray?

Do not use Fortical Nasal Spray if you are allergic to the calcitonin salmon protein.

What should I tell my doctor before using Fortical Nasal Spray?

Tell your doctor about all your health conditions, including if you:

• are pregnant. It is not known if Fortical Nasal Spray can cause harm to an unborn baby if it is used during pregnancy.
• are breast-feeding. It is not known if Fortical Nasal Spray passes into your breast milk.

Tell your doctor and pharmacist about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How should I use Fortical Nasal Spray?

• Periodic nasal exams are recommended. Your doctor should do a nasal exam before you start using Fortical Nasal Spray and if you have any nasal discomfort while using it.
• Use Fortical Nasal Spray exactly as your doctor prescribes it. See the detailed Patient Instructions for Use at the end of this leaflet.
• Before using a new bottle of Fortical Nasal Spray for the first time, take it out of the refrigerator and let the medicine warm to room temperature. Using Fortical Nasal Spray directly from a refrigerator without being warmed to room temperature may cause you to have nasal discomfort.
• Before using a new bottle of Fortical Nasal Spray for the first time, you will need to prime the pump at least 5 times until a full spray is produced. See the detailed Assembly Instructions and Using Fortical Nasal Spray sections at the end of this Patient Information Leaflet for directions on how to prime a new bottle of Fortical Nasal Spray and how to properly use Fortical Nasal Spray.
• One spray in either nostril will give you the right daily dose of Fortical Nasal Spray. Change (alternate) between using the right nostril one day and the left nostril the next day. Each bottle of Fortical Nasal Spray contains enough medicine for 30 days of dosing.
• After priming the pump, do not use Fortical Nasal Spray for more than 30 doses. Even though the container may not be completely empty, you may not get the correct dose of medicine. Safely throw away the empty bottle of Fortical Nasal Spray after you have used 30 doses.
• If you miss a dose, or forget to use Fortical Nasal Spray, use it as soon as you can. If it is almost time for your next dose, wait until then to use the medicine and skip the missed dose. Do not use extra medicine to make up for the missed dose.
• If you use too much Fortical Nasal Spray, tell your doctor.

What are the possible side effects of Fortical Nasal Spray?

Serious allergic reactions can happen with Fortical Nasal Spray. See "Who should not use Fortical Nasal Spray".

Get emergency medical help right away if you have any of the following symptoms of a serious allergic reaction:

• trouble breathing
• swelling of your face, throat or tongue
• rapid heartbeat
• chest pain
• feel faint or dizzy

The most common side effects of Fortical Nasal Spray include:

• nasal symptoms including: runny nose, dryness, crusting, sores, infection, redness, irritation, itching, tenderness, nosebleed, discomfort across bridge of nose
• back and joint pain
• headache

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Fortical Nasal Spray. For more information, ask your doctor or pharmacist.

How should I store Fortical Nasal Spray?

• Keep new, unopened bottles of Fortical Nasal Spray in the refrigerator, between 36 F to 46 F (2 C to 8 C).
• Do not freeze.
• Keep the bottle of Fortical Nasal Spray away from light.
• Allow the Fortical Nasal Spray to reach room temperature before using it and for the first time.
• Tighten the pump securely to the bottle (see Step 3 and 4 in the Patient Instructions of Use - Assembly Instructions). This will help to ensure a good seal between the pump and the bottle.
• After opening a new bottle of Fortical Nasal Spray, store at room temperature, 68 F to 77 F (20 C to 25 C).
• Each bottle of Fortical Nasal Spray contains enough medicine for 30 doses. Throw away the empty bottle of Fortical Nasal Spray after you have used 30 doses.

Keep Fortical Nasal Spray and all other medicines out of the reach of children.

What are the ingredients in Fortical Nasal Spray?

Active Ingredient: Calcitonin-salmon

Inactive Ingredients: Sodium Chloride USP, Citric Acid USP, Phenethyl Alcohol USP, Benzyl Alcohol NF, Polysorbate 80 NF, Hydrochloric Acid NF or Sodium Hydroxide NF and Purified Water USP.

General Information about Fortical Nasal Spray

This medication was prescribed for you by your doctor for a particular condition. Do not use Fortical Nasal Spray to treat a condition for which it was not prescribed. Do not give Fortical Nasal Spray to other people, even if they have the same symptoms you have. It may harm them.

This patient information leaflet summarizes the most important information about Fortical Nasal Spray. If you would like more information about Fortical Nasal Spray talk with your doctor. You can ask your doctor or pharmacist for information about Fortical Nasal Spray that is written for health professionals. For more information, go to www.upsher-smith.com or call 1-800-654-2299.

General Information about Osteoporosis

The amount of estrogen produced by a woman's body is greatly reduced after menopause. Estrogen helps to balance bone growth and keep bones strong. When estrogen is reduced, your body may remove old bone cells faster than it replaces them with new bones cells. Bones can become weak and brittle, and more likely to break (fracture). This condition is known as postmenopausal osteoporosis. Fortical Nasal Spray may increase bone density, but there is no information to show that it decreases the risk of fracture.

Patient Instructions for Use

Assembly Instructions

	Step 1. Opening the Bottle. If your pharmacist attached the pump for you, skip to step 4. Otherwise, set bottle on a flat surface like table or counter top. Hold the bottle firmly while unscrewing cap to avoid spilling any Fortical Nasal Spray.
	Step 2. Unwrapping the Pump. Carefully cut the wrapper with scissors or knife, and tear away from the pump. Be careful not to cut, bend, or touch the feed tube at bottom.
	Step 3. Attaching the Pump. Hold the bottle on a flat surface (like a table), and screw the pump onto bottle by gripping the grooves of the pump and twisting clockwise until the pump is tightly sealed to the bottle.
	Step 4. Removing Cap. To remove the cap from the pump, twist slightly while pulling up. Save the cap to replace after each use.
Save the lock tab, and push it back on to the pump after each use to avoid accidentally wasting any Fortical Nasal Spray	Step 5. Removing the Lock Tab. Grasp the lock tab between thumb and forefinger, while holding the bottle on a flat surface. Pull sideways to remove the tab and unlock the pump.
	Step 6. Prime New Pump Before First Use. Before you use a new bottle of Fortical Nasal Spray for the first time, you will need to prime it. This will ensure you get the right dose of medicine each time you use it. After you attach the pump to the bottle, and the pump and bottle have reached room temperature, you should:
Hold the bottle upright. With your index and middle fingers on each side of the top of the pump, and with your thumb under the bottle, push the pump down. Push the pump down at least 5 times, until you see a full spray. If the pump is not delivering a full spray during or after priming, contact Upsher-Smith at 1-800-654-2299. Do not place anything into the opening of the pump.

You only need to prime a new bottle. Do NOT re-prime it before each use.

Using Fortical Nasal Spray...

	Step 7. Using Fortical Nasal Spray Change (alternate) between using the right nostril one day and the left nostril the next day. Hold your head and the bottle in an upright, vertical position. Put the spray tip into your nostril at the same angle as your nasal passage.
Press the pump all the way down one time. You do not need to inhale. If you do not hold the bottle upright during use, the pump may not be able to give you the right dose of medicine. You may not feel the spray because the mist is so fine. Do not waste medication by testing the sprayer. It is all right if some of the spray drips out of your nostril. One spray will give you the correct daily dose of Fortical Nasal Spray.
	Step 8. Replace The Lock Tab After Use. Replace the lock tab to prevent wasting medication by accidently depressing the pump. Simply slide the lock tab on by pushing it sideways against the grooves in the pump.
	Step 9. Replace The Cap. Hold the top of the pump as shown in diagram 9., and slide the cap back over the tip carefully. Do NOT put the pump back in the refrigerator.

Store Fortical Nasal Spray in an upright position. Tighten the pump securely to the bottle (see Step 3 and 4 in the Patient Instructions for Use). This will help to ensure a good seal between the pump and the bottle.

Cleaning the Pump. Clean the spray tip by gently wiping it with a clean, damp cloth or tissue. Dry the tip with a cloth or tissue before replacing the cap. Do not submerse the tip or bottle in water.

Upsher-Smith Laboratories, Inc.
Minneapolis, MN USA 55447-4709
www.upsher-smith.com

Toll Free 1-800-654-2299

103001-01
Revised 0609
UPSHER-SMITH

Principal Display Panel - 2200 Iu/ml Carton ⮝

Fortical
calcitonin-salmon
(rDNA origin)
Nasal Spray

200 International Units/dose
2200 IU/mL

REFRIGERATE
UNTIL OPENED
at 36-46 F (2-8 C)

FOR INTRANASAL USE ONLY

30 doses
Each carton contains:
1 3.7 mL fill bottle and
1 spray applicator Rx only

FORTICAL calcitonin salmon spray, metered

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:54868-5499(NDC:0245-0008-35) Route of Administration NASAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CALCITONIN SALMON (UNII: 7SFC6U2VI5) (CALCITONIN SALMON - UNII:7SFC6U2VI5) CALCITONIN SALMON 2200 [iU] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE (UNII: 451W47IQ8X) CITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP) PHENETHYL ALCOHOL (UNII: ML9LGA7468) BENZYL ALCOHOL (UNII: LKG8494WBH) POLYSORBATE 80 (UNII: 6OZP39ZG8H) HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:54868-5499-0 4 in 1 CARTON 1 3.7 mL in 1 BOTTLE, SPRAY

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021406 12/30/2005

Labeler - Physicians Total Care, Inc. (194123980)

Establishment
Name	Address	ID/FEI	Business Operations
Physicians Total Care, Inc.		194123980	relabel

Revised: 1/2010 Document Id: 5855b6df-3949-4d36-b210-0fa2e5db974d 34391-3 Set id: e662c321-8c1b-4829-b4c9-459284f654c3 Version: 1 Effective Time: 20100115 Physicians Total Care, Inc.

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use FORTICAL safely and effectively. See full prescribing information for FORTICAL.

FORTICAL (calcitonin-salmon [rDNA origin]) Nasal Spray for intranasal use
Initial U.S. Approval: 2005

Recent Major Changes ⮝

Indications and Usage (1.2)	07/2014
Warnings and Precautions (5.2, 5.4)	07/2014

Dosage Forms And Strengths ⮝

• Nasal spray: 2200 International Units per mL of calcitonin-salmon in a 3.7 mL fill glass bottle with screw-on pump. Each actuation delivers 200 International 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: 7/2014

1 Indications And Usage ⮝

1.1 Treatment of Postmenopausal Osteoporosis

Fortical nasal spray is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years postmenopause. Fracture reduction efficacy has not been demonstrated. Fortical 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 Fortical nasal spray is 1 spray (200 International Units) per day intranasally, alternating nostrils daily.

2.2 Priming (Activation) of Pump

Unopened Fortical nasal spray should be stored in the refrigerator. Before using the first dose of Fortical nasal spray, the patient should wait until the bottle has reached room temperature. Remove the protective cap and clip from the bottle of Fortical nasal spray. 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 at least 5 times until a full spray is produced. The pump is primed once the first full spray is emitted. To administer, the nozzle should be carefully placed into the nostril with the patient's head in the upright position, then the pump should be firmly depressed toward the bottle. The pump should not be primed before each daily use.

2.3 Recommendations for Calcium and Vitamin D Supplementation

Patients who use Fortical 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 ⮝

Fortical 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 Upsher-Smith Laboratories, Inc. by calling toll-free at 1-888-650-3789.

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 Fortical 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 Fortical nasal spray. Use of Fortical 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 Fortical nasal spray, periodically during the course of therapy, and at any time nasal symptoms occur.

Fortical 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 Fortical 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 Fortical 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 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 Chronically

Adverse Reaction	Calcitonin-Salmon Nasal Spray N=341 % of Patients	Placebo Nasal Spray N=131 % of Patients
* 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.
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

Patients	Malignancies	Risk Difference* (%)	95% Confidence Interval (%)
* 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. The corresponding 95% confidence interval for the overall adjusted risk difference also based on MH fixed-effect method.
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 Fortical 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 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. Fortical 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, Fortical is predicted to have low probability of increasing the risk of adverse developmental outcomes above background risk.

Animal Data

Synthetic calcitonin-salmon has been shown to cause a decrease in fetal birth weights in rabbits when given by subcutaneous injection at doses 70-278 times the intranasal dose recommended for human use based on body surface area.

No embryo/fetal toxicities related to synthetic calcitonin-salmon 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 Fortical on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Because many drugs are excreted in human milk, caution should be exercised when Fortical is administered to a nursing woman. Synthetic calcitonin-salmon 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 and over. 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 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 Fortical 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.

The active ingredient in Fortical (calcitonin-salmon [rDNA origin]) nasal spray is a polypeptide of 32 amino acids manufactured by recombinant DNA technology and is identical to calcitonin-salmon produced by chemical synthesis.

This is shown by the following graphic formula:

It is provided in a 3.7 mL fill glass bottle as a solution for intranasal administration with sufficient medication for at least 30 doses. Each spray delivers 200 International Units calcitonin-salmon in a volume of 0.09 mL.

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

Inactive Ingredients: Sodium Chloride, Citric Acid, Phenylethyl Alcohol, Benzyl Alcohol, Polysorbate 80, Hydrochloric Acid or Sodium Hydroxide (added as necessary to adjust pH) and Purified Water.

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 Fortical 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 Fortical nasal spray.

Calcium Homeostasis

In two clinical studies designed to evaluate the pharmacodynamic response to calcitonin-salmon nasal spray, administration of 100-1600 International Units to healthy volunteers resulted in rapid and sustained small 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 pharmacokinetic properties of Fortical nasal spray after multiple dose administration were shown to be similar to that of a commercially available calcitonin-salmon product in healthy volunteers. Fortical nasal spray is absorbed rapidly by the nasal mucosa. In healthy volunteers approximately 3% (range 0.3%-30.6%) of a nasally administered dose is bioavailable compared to the same dose administered by intramuscular injection. Peak plasma concentrations of drug appear approximately 10 minutes after nasal administration. The terminal half-life (t1/2) of calcitonin-salmon is calculated to be about 23 minutes. There is no accumulation of the drug on repeated nasal administration at 10 hour intervals for up to 15 days. Absorption of Fortical nasal spray has not been studied in postmenopausal women.

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

	Lumbar Spine Bone Mineral Density, Mean Change From Baseline (in %) at Month 24
	Study 1 (with calcium supplement)	Study 2 (no calcium supplement)
	n (ITT) = 100	n (ITT) = 39
ITT: Intent To Treat
IU: International Units
NS: nasal spray
* p-values by parametric testing (2-tailed 2-sample t-test)
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

Fortical (calcitonin-salmon [rDNA origin]) nasal spray is presented as a metered dose solution in a 3.7 mL fill amber glass bottle with screw-on pump that contains 2200 International Units of calcitonin-salmon per mL. Following priming, the pump will deliver 200 International Units of calcitonin-salmon per activation (0.09 mL per spray). Fortical nasal spray is provided in individual boxes containing one glass bottle with screw cap and one screw-on pump (NDC# 0245-0008-35).

Storage and Handling

Store unopened bottle in refrigerator between 2 to 8 C (36 to 46 F). Protect from freezing. After opening, store bottle in use in an upright position at 20 to 25 C (68 to 77 F). Excursions permitted to 15 to 30 C (59 to 86 F). Discard the bottle after 30 doses have been used.

Principal Display Panel - 3.7 Ml Bottle Carton ⮝

NDC 0245-0008-35

FORTICAL
(calcitonin-salmon
[rDNA origin])
Nasal Spray

200 International Units/dose
2200 IU/mL

REFRIGERATE
UNTIL OPENED
at 2 to 8 C (36 to 46 F)

FOR INTRANASAL USE ONLY

30 doses
Each carton contains:
1 x 3.7 mL fill bottle and
1 spray applicator
Rx only

UPSHER-SMITH

FORTICAL calcitonin salmon spray, metered

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0245-0008 Route of Administration NASAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength calcitonin salmon (UNII: 7SFC6U2VI5) (calcitonin salmon - UNII:7SFC6U2VI5) calcitonin salmon 2200 [iU] in 1 mL

Inactive Ingredients Ingredient Name Strength sodium chloride (UNII: 451W47IQ8X) citric acid monohydrate (UNII: 2968PHW8QP) phenylethyl alcohol (UNII: ML9LGA7468) benzyl alcohol (UNII: LKG8494WBH) polysorbate 80 (UNII: 6OZP39ZG8H) hydrochloric acid (UNII: QTT17582CB) sodium hydroxide (UNII: 55X04QC32I) water (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0245-0008-35 1 in 1 CARTON 1 3.7 mL in 1 BOTTLE, SPRAY; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021406 08/12/2005

Labeler - Upsher-Smith Laboratories, Inc. (047251004)

Establishment
Name	Address	ID/FEI	Business Operations
Enteris BioPharma, Inc.		023927175	MANUFACTURE(0245-0008) , ANALYSIS(0245-0008) , API MANUFACTURE(0245-0008)

Establishment
Name	Address	ID/FEI	Business Operations
Upsher-Smith Laboratories, Inc.		079111820	REPACK(0245-0008) , LABEL(0245-0008)

Revised: 7/2014 Document Id: 2905a738-af8b-4baa-9c2f-67769897220c 34391-3 Set id: e273664a-3f6d-4ed4-9495-3fe8338e7895 Version: 10 Effective Time: 20140718 Upsher-Smith Laboratories, Inc.