CaloMist Nasal Spray

Patient Information of CaloMist Nasal Spray

No information provided. Please refer to the WARNINGS AND PRECAUTIONS section.

Description about CaloMist Nasal Spray

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.

Vitamin B₁₂ Maintenance Therapy

CaloMist 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.

Limitations Of Use

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

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

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

Dosage And Administration of CaloMist Nasal Spray

Recommended Dosage

The recommended initial dose of CaloMist 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 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 reprimed with two re-priming sprays.

Refer to Patient Labeling (Instructions for Use) for detailed information.

How Supplied the CaloMist Nasal Spray

Dosage Forms And Strengths

Nasal Spray: CaloMist (cyanocobalamin, USP) Nasal Spray is a solution of cyanocobalamin, USP, for administration as a metered spray to the nasal mucosa. Each bottle of CaloMist contains 10.7 mL of a 25 mcg of cyanocobalamin in a 0.1 mL of solution per spray. 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.

Storage And Handling

CaloMist 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. CaloMist is available as a metered dose spray in 30 mL plastic bottles containing 10.7 mL of solution. CaloMist is available in a dosage strength of 25 mcg cyanocobalamin, USP, per 0.1 mL of spray solution. One bottle delivers thirty 50 mcg doses (60 sprays) (NDC 0256-0203-01).

Storage

Store upright at room temperature between 59 °F to 86 °F (15 °C to 30 °C).

Protect from heat and light.

Protect from freezing.

Manufactured by: Fleming Pharmaceuticals, St. Louis County, MO 63026 USA. Revised: Jan 2020

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 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 B₁₂ 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 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 in an uncontrolled clinical trial.

Experience With Parenteral Vitamin B₁₂

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

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].

Drug Interactions

No Information provided

Included as part of the PRECAUTIONS section.

Precautions

Laboratory Monitoring

Obtain hematocrit, reticulocyte count, vitamin B₁₂, folate, and iron levels prior to treatment. All hematologic parameters, including vitamin B₁₂ concentrations, should be normal before initiating treatment with CaloMist. Monitor serum vitamin B₁₂ concentrations periodically to confirm adequacy of therapy. Monitor Vitamin B₁₂ concentrations and complete blood counts one month after starting CaloMist and then at 3 to 6 month intervals thereafter. Monitor methylmalonic acid and homocysteine concentrations in patients with borderline-low vitamin B₁₂ concentrations (<300 ng/L) as these are more sensitive measures of vitamin B₁₂ deficiency in this setting. Switch back to intramuscular route of administration for patients with declining or abnormally low vitamin B 12 concentrations despite maximal doses of CaloMist. Vitamin B₁₂ deficiency that is inadequately treated for longer than three months may produce irreversible neurological damage.

Use In Patients With Nasal Pathology

CaloMist has not been evaluated in patients with nasal pathology. In patients with nasal pathology, defer treatment with CaloMist 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 therapy is attempted in these patients, monitor vitamin B₁₂ concentrations 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 is not recommended for use in these patients.

Anaphylaxis And Angioedema

Anaphylactic shock, death, and angioedema were not reported in the CaloMist 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. Monitor serum potassium and platelet counts more frequently 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.

Patient Counseling Information

• Advise the patient to read the FDA-approved patient labeling (Instructions for Use)
• Important Information For Patients
• Advise patients with a chronic underlying cause of vitamin B₁₂ deficiency that they will require indefinite administration of a vitamin B₁₂ product, such as CaloMist. Noncompliance or inadequate treatment with vitamin B₁₂ therapy may result in recurrence of anemia and the development or worsening of irreversible neurological damage.
• Advise patients to separate the dosing of CaloMist and other intranasal medications by several hours.
• Advise patients that Vitamin B₁₂ levels will be monitored one month after CaloMist initiation or dose change and every 3-6 months thereafter.
• Instruct patients on how to prime the actuator and administer the dose of CaloMist. Have the patient demonstrate the administration procedure.

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. 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.

No studies have been performed to evaluate the potential of CaloMist for genotoxicity.

Animal reproduction studies assessing the effects of CaloMist on male and female fertility have not been conducted.

Use In Specific Populations

Pregnancy

Risk Summary

Administration of the approved recommended dose of CaloMist is not expected to cause major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with CaloMist nasal spray. There are risks associated with vitamin B₁₂ deficiency during pregnancy (see Clinical Considerations).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-Associated Maternal And/Or Embryo/Fetal Risk

Severe maternal vitamin B₁₂ deficiency during pregnancy may result in adverse pregnancy outcomes such as low birth weight, preterm birth and megaloblastic anemia.

Lactation

Risk Summary

Vitamin B₁₂ is present in human milk. Administration of the approved recommended dose of CaloMist is not expected to cause harm to a breastfed child. There is no information on the effects of CaloMist on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CaloMist and any potential adverse effects on the breastfed infant from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of CaloMist 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.

No Information provided

Contraindications

CaloMist is contraindicated in patients with sensitivity to cobalt, vitamin B 12, or any component of this product. Reactions following administration of parenteral vitamin B₁₂ have included: anaphylactic shock, death, and angioedema [see WARNINGS AND PRECAUTIONS].

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 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 daily for the duration of the trial; the remaining patient required doubling of the CaloMist 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 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 was initiated at Week 0
• Figure shows mean vitamin B₁₂ serum levels with 95% confidence intervals.

Pharmacokinetics

Distribution

In the blood, vitamin B₁₂ 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.