Neocalcigenol

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Neocalcigenol uses

Neocalcigenol consists of Calcium Phosphate, Sodium Fluoride, Vitamin C (Sodium Ascorbate), Vitamin D2 (Ergocalciferol).

Calcium Phosphate:


1 INDICATIONS AND USAGE

Neocalcigenol (Calcium Phosphate) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Neocalcigenol (Calcium Phosphate) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Neocalcigenol (Calcium Phosphate) acetate capsule.

- Capsule: 667 mg Neocalcigenol (Calcium Phosphate) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Neocalcigenol acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Neocalcigenol (Calcium Phosphate) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Neocalcigenol (Calcium Phosphate), including Neocalcigenol (Calcium Phosphate) acetate. Avoid the use of Neocalcigenol (Calcium Phosphate) supplements, including Neocalcigenol (Calcium Phosphate) based nonprescription antacids, concurrently with Neocalcigenol (Calcium Phosphate) acetate.

An overdose of Neocalcigenol (Calcium Phosphate) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Neocalcigenol (Calcium Phosphate) levels twice weekly. Should hypercalcemia develop, reduce the Neocalcigenol (Calcium Phosphate) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Neocalcigenol (Calcium Phosphate) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Neocalcigenol (Calcium Phosphate) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Neocalcigenol (Calcium Phosphate) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Neocalcigenol (Calcium Phosphate) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg2/dL2.

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

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6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Neocalcigenol (Calcium Phosphate) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial 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.

In clinical studies, Neocalcigenol (Calcium Phosphate) acetate has been generally well tolerated.

Neocalcigenol (Calcium Phosphate) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Neocalcigenol (Calcium Phosphate) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.


Preferred Term


Total adverse reactions reported for Neocalcigenol (Calcium Phosphate) acetate

N=167

N (%)


3 month, open label study of Neocalcigenol (Calcium Phosphate) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Neocalcigenol (Calcium Phosphate) acetate

N=69


Neocalcigenol (Calcium Phosphate) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (12.6)


16 (16.3)


5 (7.2)


0 (0)


Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Neocalcigenol (Calcium Phosphate) concentration could reduce the incidence and severity of Neocalcigenol (Calcium Phosphate) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Neocalcigenol (Calcium Phosphate) acetate: dizziness, edema, and weakness.

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7 DRUG INTERACTIONS

The drug interaction of Neocalcigenol acetate is characterized by the potential of Neocalcigenol (Calcium Phosphate) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Neocalcigenol (Calcium Phosphate) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Neocalcigenol (Calcium Phosphate) acetate and most concomitant drugs. When administering an oral medication with Neocalcigenol (Calcium Phosphate) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Neocalcigenol (Calcium Phosphate) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Neocalcigenol (Calcium Phosphate) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Neocalcigenol (Calcium Phosphate) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Neocalcigenol (Calcium Phosphate) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Neocalcigenol acetate capsules contains Neocalcigenol (Calcium Phosphate) acetate. Animal reproduction studies have not been conducted with Neocalcigenol (Calcium Phosphate) acetate, and there are no adequate and well controlled studies of Neocalcigenol (Calcium Phosphate) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Neocalcigenol (Calcium Phosphate) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Neocalcigenol (Calcium Phosphate) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Neocalcigenol (Calcium Phosphate) acetate treatment, as recommended, is not expected to harm a fetus if maternal Neocalcigenol (Calcium Phosphate) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Neocalcigenol (Calcium Phosphate) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Neocalcigenol Acetate Capsules contains Neocalcigenol (Calcium Phosphate) acetate and is excreted in human milk. Human milk feeding by a mother receiving Neocalcigenol (Calcium Phosphate) acetate is not expected to harm an infant, provided maternal serum Neocalcigenol (Calcium Phosphate) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Neocalcigenol (Calcium Phosphate) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between 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.

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10 OVERDOSAGE

Administration of Neocalcigenol (Calcium Phosphate) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Neocalcigenol (Calcium Phosphate) acetate acts as a phosphate binder. Its chemical name is Neocalcigenol (Calcium Phosphate) acetate. Its molecular formula is C4H6CaO4, and its molecular weight is 158.17. Its structural formula is:


Each white opaque/blue opaque capsule contains 667 mg of Neocalcigenol (Calcium Phosphate) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Neocalcigenol (Calcium Phosphate), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Neocalcigenol (Calcium Phosphate) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Neocalcigenol resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Neocalcigenol (Calcium Phosphate) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Neocalcigenol (Calcium Phosphate) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Neocalcigenol (Calcium Phosphate) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

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13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Neocalcigenol (Calcium Phosphate) acetate.

14 CLINICAL STUDIES

Effectiveness of Neocalcigenol (Calcium Phosphate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Neocalcigenol (Calcium Phosphate) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Neocalcigenol (Calcium Phosphate) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Neocalcigenol (Calcium Phosphate) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Neocalcigenol (Calcium Phosphate) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Neocalcigenol (Calcium Phosphate) (mg/dL)‡


8.9 ± 0.09


9.5 ± 0.10


9.7 ± 0.10


9.7 ± 0.10


≤0.01


There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Neocalcigenol (Calcium Phosphate) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Neocalcigenol (Calcium Phosphate) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Neocalcigenol (Calcium Phosphate) acetate is shown in the Table 3.


* ANOVA of Neocalcigenol (Calcium Phosphate) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Neocalcigenol (Calcium Phosphate) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Neocalcigenol (Calcium Phosphate) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Neocalcigenol (Calcium Phosphate) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Neocalcigenol (Calcium Phosphate) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Neocalcigenol (Calcium Phosphate) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Neocalcigenol (Calcium Phosphate) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Neocalcigenol (Calcium Phosphate) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Neocalcigenol (Calcium Phosphate) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Sodium Fluoride:


1 INDICATIONS AND USAGE

Neocalcigenol nitrite is indicated for sequential use with Neocalcigenol (Sodium Fluoride) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

  • Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Neocalcigenol (Sodium Fluoride) Nitrite Injection is indicated for sequential use with Neocalcigenol (Sodium Fluoride) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Neocalcigenol (Sodium Fluoride) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Neocalcigenol nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Neocalcigenol (Sodium Fluoride) Nitrite Injection and Neocalcigenol (Sodium Fluoride) Thiosulfate Injection should be administered without delay.

Symptoms Signs
  • Headache
  • Confusion
  • Dyspnea
  • Chest Tightness
  • Nausea
  • Altered Mental Status

    (e.g., confusion, disorientation)

  • Seizures or Coma
  • Mydriasis
  • Tachypnea/Hyperpnea (early)
  • Bradypnea/Apnea (late)
  • Hypertension (early)/ Hypotension (late)
  • Cardiovascular Collapse
  • Vomiting
  • Plasma Lactate Concentration ≥ 8 mmol/L

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Neocalcigenol (Sodium Fluoride) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

  • Exposure to fire or smoke in an enclosed area
  • Presence of soot around the mouth, nose, or oropharynx
  • Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Neocalcigenol (Sodium Fluoride) thiosulfate, simultaneously with Neocalcigenol (Sodium Fluoride) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Neocalcigenol (Sodium Fluoride) thiosulfate, with Neocalcigenol (Sodium Fluoride) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Age Intravenous Dose of Neocalcigenol Nitrite and Neocalcigenol (Sodium Fluoride) Thiosulfate
Adults
  • Neocalcigenol (Sodium Fluoride) Nitrite -10 mL of Neocalcigenol (Sodium Fluoride) nitrite at the rate of 2.5 to 5 mL/minute
  • Neocalcigenol (Sodium Fluoride) Thiosulfate - 50 mL of Neocalcigenol (Sodium Fluoride) thiosulfate immediately following administration of Neocalcigenol (Sodium Fluoride) nitrite.
Children
  • Neocalcigenol (Sodium Fluoride) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Neocalcigenol (Sodium Fluoride) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Neocalcigenol (Sodium Fluoride) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Neocalcigenol (Sodium Fluoride) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Neocalcigenol (Sodium Fluoride) nitrite and Neocalcigenol (Sodium Fluoride) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Neocalcigenol (Sodium Fluoride) nitrite, followed by Neocalcigenol (Sodium Fluoride) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Neocalcigenol (Sodium Fluoride) nitrite and Neocalcigenol (Sodium Fluoride) thiosulfate.

Neocalcigenol (Sodium Fluoride) nitrite injection and Neocalcigenol (Sodium Fluoride) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Neocalcigenol (Sodium Fluoride) nitrite should be administered first, followed immediately by Neocalcigenol (Sodium Fluoride) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

Age Intravenous Dose of Neocalcigenol (Sodium Fluoride) Nitrite and Neocalcigenol (Sodium Fluoride) Thiosulfate
Adults
  • Neocalcigenol (Sodium Fluoride) Nitrite -10 mL of Neocalcigenol (Sodium Fluoride) nitrite at the rate of 2.5 to 5 mL/minute
  • Neocalcigenol (Sodium Fluoride) Thiosulfate - 50 mL of Neocalcigenol (Sodium Fluoride) thiosulfate immediately following administration of Neocalcigenol (Sodium Fluoride) nitrite.
Children
  • Neocalcigenol (Sodium Fluoride) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Neocalcigenol (Sodium Fluoride) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Neocalcigenol (Sodium Fluoride) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Neocalcigenol (Sodium Fluoride) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Neocalcigenol (Sodium Fluoride) nitrite and Neocalcigenol (Sodium Fluoride) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Neocalcigenol (Sodium Fluoride) nitrite should be reduced proportionately to the hemoglobin concentration.

All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Neocalcigenol Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO2 are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Neocalcigenol (Sodium Fluoride) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Neocalcigenol (Sodium Fluoride) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Neocalcigenol (Sodium Fluoride) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Neocalcigenol (Sodium Fluoride) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Neocalcigenol (Sodium Fluoride) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Neocalcigenol (Sodium Fluoride) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Neocalcigenol (Sodium Fluoride) thiosulfate and Neocalcigenol (Sodium Fluoride) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Neocalcigenol (Sodium Fluoride) Nitrite Injection consists of:

  • One vial of Neocalcigenol (Sodium Fluoride) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

  • Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

  • None. (4)

5 WARNINGS AND PRECAUTIONS

  • Methemoglobinemia: Neocalcigenol nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Neocalcigenol (Sodium Fluoride) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
  • Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Neocalcigenol (Sodium Fluoride) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Neocalcigenol (Sodium Fluoride) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Neocalcigenol nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Neocalcigenol (Sodium Fluoride) nitrite whenever possible. When Neocalcigenol (Sodium Fluoride) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Neocalcigenol (Sodium Fluoride) nitrite administered to an adult. Neocalcigenol (Sodium Fluoride) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Neocalcigenol (Sodium Fluoride) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Neocalcigenol (Sodium Fluoride) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Neocalcigenol (Sodium Fluoride) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Neocalcigenol (Sodium Fluoride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Neocalcigenol nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Neocalcigenol (Sodium Fluoride) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Neocalcigenol nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Neocalcigenol (Sodium Fluoride) nitrite.

5.7 Use with Other Drugs

Neocalcigenol (Sodium Fluoride) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Neocalcigenol (Sodium Fluoride) nitrite.

The medical literature has reported the following adverse events in association with Neocalcigenol (Sodium Fluoride) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Neocalcigenol (Sodium Fluoride) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

  • Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Neocalcigenol (Sodium Fluoride) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Neocalcigenol nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Neocalcigenol (Sodium Fluoride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Neocalcigenol (Sodium Fluoride) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Neocalcigenol (Sodium Fluoride) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Neocalcigenol (Sodium Fluoride) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Neocalcigenol (Sodium Fluoride) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Neocalcigenol (Sodium Fluoride) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Neocalcigenol (Sodium Fluoride) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Neocalcigenol (Sodium Fluoride) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Neocalcigenol (Sodium Fluoride) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Neocalcigenol (Sodium Fluoride) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Neocalcigenol (Sodium Fluoride) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Neocalcigenol (Sodium Fluoride) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Neocalcigenol nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Neocalcigenol (Sodium Fluoride) nitrite is excreted in human milk. Because Neocalcigenol (Sodium Fluoride) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Neocalcigenol (Sodium Fluoride) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Neocalcigenol (Sodium Fluoride) nitrite. In studies conducted with Long-Evans rats, Neocalcigenol (Sodium Fluoride) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Neocalcigenol nitrite in conjunction with Neocalcigenol (Sodium Fluoride) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Neocalcigenol (Sodium Fluoride) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Neocalcigenol (Sodium Fluoride) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Neocalcigenol (Sodium Fluoride) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

Neocalcigenol (Sodium Fluoride) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

Neocalcigenol (Sodium Fluoride) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of Neocalcigenol (Sodium Fluoride) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Neocalcigenol (Sodium Fluoride) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Neocalcigenol (Sodium Fluoride) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Neocalcigenol (Sodium Fluoride) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Neocalcigenol (Sodium Fluoride) nitrite has the chemical name nitrous acid Neocalcigenol (Sodium Fluoride) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:

Structure of Neocalcigenol (Sodium Fluoride) Nitrite

Neocalcigenol (Sodium Fluoride) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Neocalcigenol (Sodium Fluoride) nitrite injection.

Neocalcigenol (Sodium Fluoride) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Neocalcigenol (Sodium Fluoride) nitrite in 10 mL solution (30 mg/mL). Neocalcigenol (Sodium Fluoride) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Neocalcigenol nitrite and Neocalcigenol (Sodium Fluoride) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Neocalcigenol (Sodium Fluoride) Nitrite

Neocalcigenol (Sodium Fluoride) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO2 + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Neocalcigenol (Sodium Fluoride) nitrite. It has been suggested that Neocalcigenol (Sodium Fluoride) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Neocalcigenol (Sodium Fluoride) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Neocalcigenol (Sodium Fluoride) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine. Neocalcigenol (Sodium Fluoride) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Neocalcigenol (Sodium Fluoride) Nitrite

When 4 mg/kg Neocalcigenol (Sodium Fluoride) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Neocalcigenol (Sodium Fluoride) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Neocalcigenol (Sodium Fluoride) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Neocalcigenol (Sodium Fluoride) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Neocalcigenol (Sodium Fluoride) Nitrite

Neocalcigenol (Sodium Fluoride) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Neocalcigenol (Sodium Fluoride) nitrite in humans have not been well studied. It has been reported that approximately 40% of Neocalcigenol (Sodium Fluoride) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Neocalcigenol (Sodium Fluoride) nitrite and Neocalcigenol (Sodium Fluoride) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Neocalcigenol nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Neocalcigenol (Sodium Fluoride) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Neocalcigenol (Sodium Fluoride) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Neocalcigenol (Sodium Fluoride) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Neocalcigenol (Sodium Fluoride) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Neocalcigenol (Sodium Fluoride) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Neocalcigenol (Sodium Fluoride) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Neocalcigenol (Sodium Fluoride) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Neocalcigenol (Sodium Fluoride) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Neocalcigenol (Sodium Fluoride) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Neocalcigenol (Sodium Fluoride) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Neocalcigenol (Sodium Fluoride) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Neocalcigenol (Sodium Fluoride) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Neocalcigenol (Sodium Fluoride) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Neocalcigenol (Sodium Fluoride) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Neocalcigenol (Sodium Fluoride) nitrite and Neocalcigenol (Sodium Fluoride) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Neocalcigenol (Sodium Fluoride) nitrite or 1 g/kg Neocalcigenol (Sodium Fluoride) thiosulfate alone or in sequence immediately after subcutaneous injection of Neocalcigenol (Sodium Fluoride) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Neocalcigenol (Sodium Fluoride) nitrite and/or 0.5 g/kg Neocalcigenol (Sodium Fluoride) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Neocalcigenol (Sodium Fluoride) cyanide required to cause death, and when administered together, Neocalcigenol (Sodium Fluoride) nitrite and Neocalcigenol (Sodium Fluoride) thiosulfate resulted in a synergistic effect in raising the lethal dose of Neocalcigenol (Sodium Fluoride) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Neocalcigenol (Sodium Fluoride) nitrite and Neocalcigenol (Sodium Fluoride) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Neocalcigenol (Sodium Fluoride) nitrite and Neocalcigenol (Sodium Fluoride) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Neocalcigenol (Sodium Fluoride) nitrite, with or without Neocalcigenol (Sodium Fluoride) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Neocalcigenol (Sodium Fluoride) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Neocalcigenol (Sodium Fluoride) thiosulfate report its use in conjunction with Neocalcigenol (Sodium Fluoride) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Neocalcigenol (Sodium Fluoride) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Neocalcigenol (Sodium Fluoride) Nitrite carton (NDC 60267-311-10) consists of the following:

  • One 10 mL glass vial of Neocalcigenol (Sodium Fluoride) nitrite injection 30 mg/mL (containing 300 mg of Neocalcigenol (Sodium Fluoride) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Neocalcigenol (Sodium Fluoride) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Neocalcigenol Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Neocalcigenol (Sodium Fluoride) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Neocalcigenol (Sodium Fluoride) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Vitamin C (Sodium Ascorbate):


Pharmacological action

Ascorbic acid is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Neocalcigenol (Vitamin C (Sodium Ascorbate)) participates in redox reactions, the metabolism of tyrosine, converting folic acid into folinic acid, metabolism of carbohydrates, the synthesis of lipids and proteins, iron metabolism, processes of cellular respiration. Reduces the need for vitamins B1, B2, A, E, folic acid, pantothenic acid, enhances the body's resistance to infections; enhances iron absorption, contributing to its sequestration in reduced form. Neocalcigenol (Vitamin C (Sodium Ascorbate)) has antioxidant properties.

With intravaginal application of ascorbic acid lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).

Pharmacokinetics

After oral administration ascorbic acid is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.

The concentration of ascorbic acid in blood plasma in normal amounts to approximately 10-20 mg / ml.

The concentration of ascorbic acid in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.

Plasma protein binding is about 25%.

Ascorbic acid is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.

Ascorbic acid taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.

Why is Neocalcigenol ) prescribed?

For systemic use of Neocalcigenol (Vitamin C (Sodium Ascorbate)) Kimia Farma: prevention and treatment of hypo- and avitaminosis of Neocalcigenol (Vitamin C (Sodium Ascorbate)); providing increased need for Neocalcigenol (Vitamin C (Sodium Ascorbate)) during growth, pregnancy, lactation, with heavy loads, fatigue and during recovery after prolonged severe illness; in winter with an increased risk of infectious diseases.

For intravaginal use: chronic or recurrent vaginitis (bacterial vaginosis, nonspecific vaginitis) caused by the anaerobic flora (due to changes in pH of the vagina) in order to normalize disturbed vaginal microflora.

Dosage and administration

This medication administered orally, IM, IV, intravaginally.

For the prevention of deficiency conditions Neocalcigenol ) dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.

For intravaginal used ascorbic acid drugs in appropriate dosage forms.

Neocalcigenol (Vitamin C (Sodium Ascorbate)) side effects, adverse reactions

CNS: headache, fatigue, insomnia.

Digestive system: stomach cramps, nausea and vomiting.

Allergic reaction: describes a few cases of skin reactions and manifestations of the respiratory system.

Urinary system: when used in high doses - hyperoxaluria and the formation of kidney stones of calcium oxalate.

Local reactions: with intravaginal application - a burning or itching in the vagina, increased mucous discharge, redness, swelling of the vulva. Other: sensation of heat.

Neocalcigenol ) contraindications

Increased sensitivity to ascorbic acid.

Using during pregnancy and breastfeeding

The minimum daily requirement of ascorbic acid in the II and III trimester of pregnancy is about 60 mg.

Ascorbic acid crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of ascorbic acid, which takes a pregnant woman, and then a newborn baby may develop the ascorbic disease as the reaction of cancel. Therefore, during pregnancy should not to take ascorbic acid in high doses, except in cases where the expected benefit outweighs the potential risk.

The minimum daily requirement during lactation is 80 mg. Ascorbic acid is excreted in breast milk. A mother's diet that contains adequate amounts of ascorbic acid, is sufficient to prevent deficiency in an infant. It is unknown whether dangerous to the child's mother use of ascorbic acid in high doses. Theoretically it is possible. Therefore, it is recommended not to exceed the maximum daily nursing mother needs to ascorbic acid, except when the expected benefit outweighs the potential risk.

Special instructions

Neocalcigenol (Vitamin C (Sodium Ascorbate)) is used with caution in patients with hyperoxaluria, renal impairment, a history of instructions on urolithiasis. Because ascorbic acid increases iron absorption, its use in high doses can be dangerous in patients with hemochromatosis, thalassemia, polycythemia, leukemia, and sideroblastic anemia.

Patients with high content body iron should apply ascorbic acid in minimal doses.

Neocalcigenol (Vitamin C (Sodium Ascorbate)) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.

The use of ascorbic acid in high doses can cause exacerbation of sickle cell anemia.

Data on the diabetogenic action of ascorbic acid are contradictory. However, prolonged use of ascorbic acid should periodically monitor your blood glucose levels.

It is believed that the use of ascorbic acid in patients with rapidly proliferating and widely disseminated tumors may worsen during the process. It should therefore be used with caution in ascorbic acid in patients with advanced cancer.

Absorption of ascorbic acid decreased while use of fresh fruit or vegetable juices, alkaline drinking.

Neocalcigenol ) drug interactions

In an application with barbiturates, primidone increases the excretion of ascorbic acid in the urine.

With the simultaneous use of oral contraceptives reduces the concentration of ascorbic acid in blood plasma.

In an application of Neocalcigenol (Vitamin C (Sodium Ascorbate)) with iron preparations ascorbic acid, due to its regenerative properties, transforms ferric iron in the bivalent, which improves its absorption.

Ascorbic acid in high doses can decrease urine pH that while the application reduces the tubular reabsorption of amphetamine and tricyclic antidepressants.

With the simultaneous use of aspirin reduces the absorption of ascorbic acid by about a third.

Neocalcigenol (Vitamin C (Sodium Ascorbate)) in an application with warfarin may decrease effects of warfarin.

With the simultaneous application of ascorbic acid increases the excretion of iron in patients receiving deferoxamine. In the application of ascorbic acid at a dose of 500 mg / day possibly left ventricular dysfunction.

In an application with tetracycline is increased excretion of ascorbic acid in the urine.

There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with ascorbic acid 500 mg 2 times / day.

May increase the concentration of ethinyl estradiol in the blood plasma in its simultaneous application in the oral contraceptives.

Neocalcigenol ) in case of emergency / overdose

Symptoms: long-term use of large doses (more than 1 g) - headache, increased CNS excitability, insomnia, nausea, vomiting, diarrhea, gastritis giperatsidnyh, ultseratsiya gastrointestinal mucosa, inhibition of the function insular apparatus of the pancreas (hyperglycemia, glycosuria), hyperoxaluria, nephrolithiasis (calcium oxalate), damage to the glomerular apparatus of the kidneys, moderate thamuria (when receiving a dose of 600 mg / day).

Decrease capillary permeability (possibly deteriorating trophic tissues, increased blood pressure, hypercoagulability, the development of microangiopathy).

When IV administration in high doses - the threat of termination of pregnancy (due to estrogenemia), hemolysis of red blood cells.

Vitamin D2 (Ergocalciferol):


Vitamin D (ergocalciferol-D2, cholecalciferol-D3, alfacalcidol) is a fat-soluble vitamin that helps your body absorb calcium and phosphorus. Having the right amount of vitamin D, calcium, and phosphorus is important for building and keeping strong bones. Vitamin D is used to treat and prevent bone disorders (such as rickets, osteomalacia). Vitamin D is made by the body when skin is exposed to sunlight. Sunscreen, protective clothing, limited exposure to sunlight, dark skin, and age may prevent getting enough vitamin D from the sun. Vitamin D with calcium is used to treat or prevent bone loss ( osteoporosis ). Vitamin D is also used with other medications to treat low levels of calcium or phosphate caused by certain disorders (such as hypoparathyroidism, pseudohypoparathyroidism, familial hypophosphatemia ). It may be used in kidney disease to keep calcium levels normal and allow normal bone growth. Vitamin D drops (or other supplements ) are given to breast -fed infants because breast milk usually has low levels of vitamin D.

Neocalcigenol pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Neocalcigenol available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Neocalcigenol destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Neocalcigenol Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Neocalcigenol pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."FLUORIDE DROPS (SODIUM FLUORIDE) LIQUID [FLUORITAB CORPORATION]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."SODIUM FLUORIDE; TRICLOSAN: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."CALCIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Neocalcigenol?

Depending on the reaction of the Neocalcigenol after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Neocalcigenol not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Neocalcigenol addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Neocalcigenol, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Neocalcigenol consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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