Cyanocobalamin is a synthetic form of vitamin B₁₂ with activity equivalent to the endogenous form of vitamin B₁₂. The chemical name is α-(5,6-dimethylbenzimidazolyl) cyanocobamide. The cobalt content is 4.35%. The molecular formula is C₆₃H₈₈CoN₁₄O₁₄P, which corresponds to a molecular weight of 1355.4 and the following structural formula:

Cyanocobalamin occurs as dark red crystals, orthorhombic needles, or crystalline red powder and is very hygroscopic in the anhydrous form, and sparingly to moderately soluble in water (1:80). The pharmacologic activity of cyanocobalamin is destroyed by heavy metals (iron) and strong oxidizing or reducing agents (Vitamin C), but not by autoclaving for short periods of time (15-20 minutes) at 121° C. The vitamin B₁₂ coenzymes are very unstable in light.

Each bottle of CaloMist Nasal Spray contains cyanocobalamin, sodium chloride, sodium phosphate monobasic, benzyl alcohol, sodium hydroxide, and benzalkonium chloride in purified water with an attached spray pump unit.

Last updated on RxList: 8/16/2007

Vitamin B₁₂ Deficiency

CaloMist Nasal Spray is indicated for maintenance of vitamin B₁₂ concentrations after normalization with intramuscular vitamin B₁₂ therapy in patients with vitamin B₁₂ deficiency who have no nervous system involvement.

Important Limitations of Use

CaloMist Nasal Spray has not been evaluated for the treatment of newly diagnosed vitamin B₁₂ deficiency.

CaloMist Nasal Spray is not suitable for use in the vitamin B₁₂ absorption test (Schilling Test).

The effectiveness of CaloMist Nasal Spray in patients with nasal pathology (e.g., nasal congestion, allergic rhinitis, upper respiratory infections) has not been determined. Treatment with CaloMist Nasal Spray should be deferred until nasal symptoms have subsided [see WARNINGS and PRECAUTIONS].

Recommended Dose

The recommended initial dose of CaloMist Nasal Spray is one spray in each nostril once daily (25 mcg per nostril, total daily dose 50 mcg). The dose should be increased to one spray in each nostril twice daily (total daily dose 100 mcg) for patients with an inadequate response to once daily dosing.

The dosing of CaloMist Nasal Spray and other intranasal medications should be separated by several hours, and these patients should have more frequent monitoring of vitamin B₁₂ concentrations because of the potential for erratic absorption.

Priming (Activation) of Pump

The pump must be primed before the bottle is used for the first time. To prime the pump, place the nozzle between the first and second finger with the thumb on the bottom of the bottle. Pump the unit firmly and quickly then repeat this priming an additional 6 times for a total of 7 priming sprays. Now the nasal spray is ready for first-time use. If 5 or more days elapse since last use, the pump must be re-primed with two re-priming sprays.

Additional instructions are provided in the patient instruction sheet [see Patient Counseling Information].

Dosage Forms and Strengths

CaloMist Nasal Spray (cyanocobalamin, USP) is a solution of cyanocobalamin, USP, for administration as a metered spray to the nasal mucosa. Each bottle of CaloMist Nasal Spray contains 18 mL of a 25 mcg/0.1 mL solution of cyanocobalamin. The spray solution has a pH between 6.5 and 7.5. After initial priming, each spray delivers 25 mcg of cyanocobalamin. Each bottle will deliver 60 sprays for a total of thirty 50 mcg doses of CaloMist Nasal Spray.

AND STORAGE AND HANDLING

CaloMist Nasal Spray is available as a metered dose spray in 30 mL plastic bottles containing 18 mL of solution. CaloMist Nasal Spray is available in a dosage strength of 25 mcg cyanocobalamin, USP, per actuation (0.1 mL/actuation). CaloMist Nasal Spray is provided in a carton containing one bottle of nasal spray solution affixed with a nasal spray pump, a package insert, and a patient instruction sheet. One bottle delivers thirty 50 mcg doses (60 sprays) (NDC 0256-0203-01).

Storage

Protect from light. Store upright at a controlled temperature of 15 to 30° C (59 to 86° F).

Protect from freezing.

Manufactured by: Fleming Pharmaceuticals., Fenton, MO 63026 USA
calomist@flemingcompany.com., 1-800-343-0164. FDA rev date: 7/27/2007

Last updated on RxList: 8/16/2007

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 data described below and in Table 1 reflect exposure in 25 subjects (age range 27-82 years; 17 women; 21 Caucasians) with vitamin B₁₂ deficiency (12 with pernicious anemia, 4 secondary to gastrointestinal surgery, 9 with unknown cause) who received CaloMist Nasal Spray 50 mcg daily for 8 weeks in an uncontrolled clinical trial. Prior to enrollment, all subjects were required to have normal vitamin B₁₂ levels with intramuscular vitamin BI2 injections. One patient who completed the study developed epistaxis on Day 12 of dosing and was noted to have irritation of the right nasal septum at study end. This patient had pre-existing allergic rhinitis and required a doubling of the CaloMist Nasal Spray dose during the last week of the study because of declining vitamin B₁₂ concentrations.

Table 1. Potentially related adverse reactions reported during 8 weeks of treatment with CaloMist Nasal Spray in an uncontrolled clinical trial.

Preferred Term	CaloMist Nasal Spray (N=25) n (%)
Arthralgia	3 (12%)
Dizziness	3 (12%)
Headache	3 (12%)
Nasopharyngitis	3 (12%)
Rhinorrhea	3 (12%)
Bronchitis	2 (8%)
Nasal Discomfort	2 (8%)
Pain	2 (8%)
Rash	2 (8%)
Asthma	1 (4%)
Back Pain	1 (4%)
Cough	1 (4%)
Epistaxis	1 (4%)
Hypersomnia	1 (4%)
Influenza Like Illness	1 (4%)
Malaise	1 (4%)
Pharyngolaryngeal Pain	1 (4%)
Postnasal Drip	1 (4%)
Procedural Pain	1 (4%)
Pyrexia	1 (4%)
Scab	1 (4%)
Sinus Headache	1 (4%)
Sinusitis	1 (4%)
Tooth Abscess	1 (4%)

Experience with Parenteral Vitamin B₁₂

The following adverse reactions have been reported with parenteral vitamin B₁₂:

Generalized: Anaphylactic shock and death

Cardiovascular: Pulmonary edema and congestive heart failure early in treatment Peripheral vascular thrombosis

Hematological : Polycythemia vera

Gastrointestinal: Mild transient diarrhea Dermatological: Itching; transitory exanthema

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of cyanocobalamin. Because these 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.

Angioedema and angioedema-like reactions [See WARNINGS and PRECAUTIONS]

Most antibiotics, methotrexate, and pyrimethamine invalidate the vitamin B₁₂ diagnostic blood assays.

Last updated on RxList: 8/16/2007

Included as part of the PRECAUTIONS section.

Laboratory Monitoring

Hematocrit, reticulocyte count, vitamin B₁₂, folate, and iron levels should be obtained prior to treatment. All hematologic parameters, including vitamin B₁₂ concentrations, should be normal before initiating treatment with CaloMist Nasal Spray. Periodic monitoring of serum vitamin B₁₂ concentrations must be obtained to confirm adequacy of therapy. Vitamin B₁₂ concentrations and complete blood counts should be monitored one month after starting CaloMist Nasal Spray and then at 3 to 6 month intervals thereafter. Patients with borderline-low vitamin B₁₂ concentrations (<300 ng/L) should also undergo measurement of methylmalonic acid and homocysteine concentrations, which are more sensitive measures of vitamin B₁₂ deficiency in this setting.

Patients with declining or abnormally low vitamin B₁₂ concentrations despite maximal doses of CaloMist Nasal Spray should be switched back to intramuscular vitamin B₁₂ injections. Vitamin B₁₂ deficiency that is inadequately treated for longer than three months may produce irreversible neurological damage.

Use in Patients With Nasal Pathology

CaloMist Nasal Spray has not been evaluated in patients with nasal pathology. Treatment with CaloMist Nasal Spray should be deferred until nasal symptoms have subsided. Patients with chronic nasal symptoms or significant nasal pathology are not ideal candidates for intranasal vitamin B₁₂ therapy. If CaloMist Nasal Spray therapy is attempted in these patients, vitamin B₁₂ concentrations should be monitored more frequently than in patients without nasal pathology because of the potential for erratic or blunted absorption.

Use in Patients with Leber's Disease

Patients with early Leber's disease (hereditary optic nerve atrophy) who were treated with cyanocobalamin suffered severe and swift optic atrophy. Cyanocobalamin should not be used in these patients.

Anaphylaxis and Angioedema

Anaphylactic shock, death, and angioedema were not reported in the CaloMist Nasal Spray clinical trial but have been reported with parenteral vitamin B₁₂ administration.

Megaloblastic Anemia

Megaloblastic anemia has many causes, including vitamin B₁₂ deficiency and folate deficiency. Folic acid may result in a hematological response in patients with vitamin B₁₂ deficiency, but will not prevent irreversible neurological manifestations. Vitamin B₁₂ is not an appropriate treatment for folate deficiency.

Hypokalemia, thrombocytosis, and sudden death may occur when severe megaloblastic anemia is treated intensely with vitamin B₁₂. Serum potassium and the platelet count should be carefully monitored in this setting.

Blunted Response to Vitamin B₁₂ Therapy

Infections, uremia, concurrent iron or folic acid deficiency, and drugs with bone marrow suppressant properties (e.g., chloramphenicol) may blunt the therapeutic response to vitamin B₁₂ products, including CaloMist Nasal Spray.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

There are no long-term studies in animals that have evaluated the carcinogenic potential of any of the vitamin B₁₂ products, including CaloMist Nasal Spray. There is no evidence from long-term use in patients with pernicious anemia that vitamin B₁₂ is carcinogenic. Pernicious anemia is associated with an increased incidence of carcinoma of the stomach, but this malignancy has been attributed to the underlying pathology of pernicious anemia and not to treatment with vitamin B₁₂.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with CaloMist Nasal Spray. Although vitamin B₁₂ is an essential vitamin and requirements are increased during pregnancy, it is not known whether CaloMist Nasal Spray can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CaloMist Nasal Spray should be given to a pregnant woman only if clearly needed. Adequate and well-controlled studies have not been conducted in pregnant women.

Nursing Mothers

Although vitamin B₁₂ is an essential vitamin and requirements are increased during lactation, it is not known whether CaloMist Nasal Spray can cause harm to an infant when administered to a nursing woman. Vitamin B₁₂ appears in the milk of nursing mothers in concentrations that approximate the mother's vitamin B₁₂ blood level. Caution should be exercised when CaloMist Nasal Spray is administered to a nursing woman.

Pediatric Use

Because CaloMist Nasal Spray has not been studied in children, safety and effectiveness have not been established in pediatric patients.

Geriatric Use

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

Renal/Hepatic Impairment

Patients with vitamin B₁₂ deficiency and concurrent renal or hepatic disease may require increased doses or more frequent administration of vitamin B₁₂ therapy.

Last updated on RxList: 8/16/2007

No information provided.

Sensitivity to cobalt, vitamin B₁₂, or any component of this product [see WARNINGS and PRECAUTIONS].

Last updated on RxList: 8/16/2007

Mechanism of Action

Vitamin B₁₂ is essential for growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Rapidly dividing cells (e.g., epithelial cells, bone marrow, myeloid cells) have the greatest requirement for vitamin B₁₂. In tissues, vitamin B₁₂ is essential for the conversion of methylmalonate to succinate and for the synthesis of methionine from homocysteine. In the absence of vitamin B₁₂, tetrahydrofolate cannot be regenerated from 5-methyl tetrahydrofolate, and functional folate deficiency occurs. Vitamin B₁₂ also may be involved in sulfhydryl-activated enzyme systems associated with fat and carbohydrate metabolism and protein synthesis.

Pharmacodynamics

In 24 vitamin B₁₂ deficient patients who were stabilized on intramuscular (IM) vitamin B₁₂ therapy, once daily intranasal dosing with CaloMist Nasal Spray for 8 weeks resulted in serum vitamin B₁₂ concentrations that were within the target range (>200 ng/L) and slightly higher than those seen 2 to 4 weeks after administration of IM vitamin B₁₂ (see Figure 1 - average mean increase from Visit 1 to Visits 3-6 = 45 ng/L). Twenty-three of these 24 patients received 50 mcg of CaloMist Nasal Spray daily for the duration of the trial; the remaining patient required doubling of the CaloMist Nasal Spray dose from 50 mcg to 100 mcg daily during the last week of the study because of declining vitamin B₁₂ concentrations. One of the 25 patients dosed with CaloMist Nasal Spray was excluded from the efficacy analyses because a diagnosis of vitamin B₁₂ deficiency could not be confirmed.

Figure 1 : Mean Vitamin B₁₂ Serum Levels Over 8 Weeks of Intranasal (IN) Vitamin B₁₂ Dosing in 24 Subjects Stabilized on Intramuscular (IM) Vitamin B₁₂

Notes:

- Weeks -2 to -4 correspond to 2 to 4 weeks post last IM injection
- CaloMist Nasal Spray was initiated at Week 0.
- Figure shows mean vitamin B₁₂ serum levels with 95% confidence intervals.

Pharmacokinetics Distribution

In the blood, vitamin BI2 is bound to transcobalamin II (a specific B-globulin carrier protein) and is distributed to tissues and stored primarily in the liver and bone marrow.

Elimination

About 3-8 mcg of vitamin B₁₂ is secreted into the gastrointestinal tract daily via the bile. In subjects with sufficient intrinsic factor, all but about 1 mcg is reabsorbed. When vitamin B₁₂ is administered in doses that saturate the binding capacity of plasma proteins and the liver, the unbound vitamin B₁₂ is rapidly eliminated in the urine. Retention of vitamin B₁₂ in the body is dose-dependent.

Last updated on RxList: 8/16/2007

PATIENT COUNSELING INFORMATION

[See FDA-approved Patient Labeling]

Important Information for Patients

Patients with a chronic underlying cause of vitamin B₁₂ deficiency will require indefinite administration of a vitamin B₁₂ product, such as CaloMist Nasal Spray. Noncompliance or inadequate treatment with vitamin B₁₂ therapy may result in recurrence of anemia and the development or worsening of irreversible neurological damage.

The dosing of CaloMist Nasal Spray and other intranasal medications should be separated by several hours.

Vitamin B₁₂ concentrations should be monitored one month after CaloMist Nasal Spray initiation or dose change and every 3-6 months thereafter.

Careful instructions on the priming of the actuator and nasal administration of CaloMist Nasal Spray should be given to the patient, and the procedures for use should be demonstrated.

Patient Instruction Sheet

Instructions for Using CaloMist Nasal Spray. Read the following instructions carefully before using CaloMist Nasal Spray.

• Use CaloMist Nasal Spray as directed by your doctor.

NOTE: CaloMist Nasal Spray is prefilled to give 30 doses (60 sprays of medicine). One dose is one spray in each nostril once a day.

CaloMist Nasal Spray Pump Priming: Before you use the medicine for the first time the nasal spray pump unit must be readied (primed).

1. Hold the nasal spray bottle upright with your index finger on top of one of the two arms of the pump. Remove the clear protective cap from the top of the nozzle. (See Diagram 1)

2. Remove the safety clip from the nasal spray pump. (See Diagram 1)

3. While holding the nasal spray bottle upright with your index and middle fingers on the two side arms of the pump, and your thumb on the bottom of the bottle, press the arms down firmly and quickly. (See Diagram 2)

4. Repeat Step 3, 6 more times for a total of 7 priming sprays. You should see a full spray of medicine with the 7th priming spray. (See Diagram 2)

NOTE: You must prime CaloMist Nasal Spray with two re-priming sprays if you do not use for five days or more.

Your CaloMist Nasal Spray is now ready to use.

1. Blow your nose gently to clear both nostrils. (See Diagram 3)

2. Hold the nasal spray bottle upright with your first and second fingers on the two side arms of the pump, and your thumb on the bottom of the bottle. (See Diagram 4)

3. Gently insert the nasal spray pump to one nostril (about ½ inch), pointing the tip towards the back of the nose. (See Diagram 4)

4. With your other hand (the one not holding the bottle) use a finger to gently push close your other nostril (the one without a spray pump inserted). (See Diagram 4)

5. Tilt your head forward and press the arms of the nasal spray bottle down firmly and quickly.

6. Sniff in gently during and right after a spray and return your head to an upright position. Repeat these steps for the other nostril.

7. Wipe the nozzle of the nasal spray pump with a clean tissue after use. Replace the safety clip and clear cover on the nasal spray pump.

8. Store CaloMist Nasal Spray upright at room temperature, 59 to 86° F (15 to 30° C). Do not freeze.

Discard CaloMist Nasal Spray after 30 doses (60 sprays).

1. Unscrew the cap, rinse the bottle and pump assembly under a water faucet.
2. Dispose of all parts in a trashcan.

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

Last updated on RxList: 8/16/2007

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

CYANOCOBALAMIN - NASAL

(SYE-an-oh-koe-BAL-a-min)

COMMON BRAND NAME(S): Nascobal

USES: Cyanocobalamin is a man-made form of vitamin B12 used to treat low levels (deficiency) of this vitamin. Vitamin B12 helps your body use fat and carbohydrates for energy and make new protein. It is also important for normal blood, cells, and nerves. Most people get enough vitamin B12 in their diet, but a deficiency may occur in certain health conditions (e.g., poor nutrition, pregnancy, stomach/intestinal problems, infection, cancer). Serious vitamin B12 deficiency may result in anemia, stomach problems, and nerve damage.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using this medication and each time you get a refill. Refer to the illustrated instructions provided by the manufacturer for directions on how to use this device. If any of the information is unclear, consult your doctor or pharmacist.

Gently blow your nose before using this drug. Follow the instructions on how to properly prime the bottle if you are using it for the first time. The gel pump does not need to be primed after the first use. However, the spray pump must be primed with each use.

Use this medication in the nose once weekly or as directed by your doctor. Hot food or drinks may produce mucus that can wash away this medication. Therefore, avoid hot food or drinks for 1 hour before or after using this medication.

Dosage is based on your medical condition and response to treatment. Do not increase, decrease, or stop this medication without your doctor's approval. Use this medication regularly to get the most benefit from it. To help you remember, use it on the same day each week. It may help to mark your calendar with a reminder.

SIDE EFFECTS: Headache, nausea, or runny nose may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This medication may cause low potassium levels in the blood (hypokalemia). Tell your doctor immediately if any of these unlikely but serious side effects occur: muscle cramps, weakness, irregular heartbeat.

People who have a rare blood disorder (polycythemia vera) may infrequently have symptoms related to this disorder while taking cyanocobalamin. Seek immediate medical attention if any of these rare but very serious symptoms occur: chest pain (especially with shortness of breath), weakness on one side of the body, sudden vision changes, slurred speech.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, swelling (especially of face/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using cyanocobalamin, tell your doctor or pharmacist if you are allergic to it; or to cobalt; or if you have any other allergies. Your doctor may recommend that you receive a smaller test dose before starting your regular dose. Consult your doctor or pharmacist for more information.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: low potassium blood levels (hypokalemia), gout, a certain blood disorder (polycythemia vera), a certain eye disease (Leber's disease), other vitamin/mineral deficiencies (especially folic acid and iron).

Tell your doctor if you develop a stuffy or runny nose (e.g., due to a common cold or allergies) while using this medication. You may need to use another form of vitamin B12 when these symptoms are present.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

Based on information from related drugs, this medication may pass into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs that may affect blood cell production (e.g., chloramphenicol, anti-cancer drugs, HIV drugs), other vitamins/nutritional supplements (especially folic acid).

Certain other drugs may interfere with laboratory tests for vitamin B12 levels, possibly causing false test results. Tell laboratory personnel and all your doctors if you take any of the following: anti-infective drugs (e.g., amoxicillin, erythromycin), methotrexate, pyrimethamine.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: Overdose with this medication is very unlikely. However, if overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., serum potassium levels, complete blood count, hematocrit, vitamin B12 levels) should be performed to monitor your progress or check for side effects. Consult your doctor for more details.

This product is not a substitute for a proper diet. Remember that it is best to get your vitamins from healthy foods. Vitamin B12 is commonly found in many foods from animals, especially liver, kidney, fish and shellfish, meat, and dairy foods.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store the pump upright at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not freeze. Do not store in the bathroom. Keep track of the number of doses you use from each pump, and discard the pump after you have used the labeled number of doses on the product package. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.