For Intranasal Use Only

Rx only

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.

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.

Clinical allergy to calcitonin-salmon.

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).

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.

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.

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.

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).

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

Patient Information and Instructions for Use

Patient Information

Fortical® [fōr-tǐ-kǎl]
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

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