DRUGS & SUPPLEMENTS

Nutrineal PD4

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Nutrineal PD4 uses

Nutrineal PD4 consists of Calcium Chloride Dihydrate, Glycine, L-Alanine, L-Arginine, L-Histidine, L-Isoleucine, L-Leucine, L-Lysine Hydrochloride, L-Methionine, L-Phenylalanine, L-Proline, L-Serine, L-Threonine, L-Tryptophan, L-Tyrosine, L-Valine, Magnesium Chloride Hexahydrate, Sodium Chloride, Sodium Lactate.

Calcium Chloride Dihydrate:


1 INDICATIONS AND USAGE

Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) acetate capsule.

- Capsule: 667 mg Nutrineal PD4 (Calcium Chloride Dihydrate) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Nutrineal PD4 acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate), including Nutrineal PD4 (Calcium Chloride Dihydrate) acetate. Avoid the use of Nutrineal PD4 (Calcium Chloride Dihydrate) supplements, including Nutrineal PD4 (Calcium Chloride Dihydrate) based nonprescription antacids, concurrently with Nutrineal PD4 (Calcium Chloride Dihydrate) acetate.

An overdose of Nutrineal PD4 (Calcium Chloride Dihydrate) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Nutrineal PD4 (Calcium Chloride Dihydrate) levels twice weekly. Should hypercalcemia develop, reduce the Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) 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, Nutrineal PD4 (Calcium Chloride Dihydrate) acetate has been generally well tolerated.

Nutrineal PD4 (Calcium Chloride Dihydrate) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) acetate

N=167

N (%)


3 month, open label study of Nutrineal PD4 (Calcium Chloride Dihydrate) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Nutrineal PD4 (Calcium Chloride Dihydrate) acetate

N=69


Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) concentration could reduce the incidence and severity of Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) acetate: dizziness, edema, and weakness.

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7 DRUG INTERACTIONS

The drug interaction of Nutrineal PD4 acetate is characterized by the potential of Nutrineal PD4 (Calcium Chloride Dihydrate) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Nutrineal PD4 (Calcium Chloride Dihydrate) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Nutrineal PD4 (Calcium Chloride Dihydrate) acetate and most concomitant drugs. When administering an oral medication with Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Nutrineal PD4 acetate capsules contains Nutrineal PD4 (Calcium Chloride Dihydrate) acetate. Animal reproduction studies have not been conducted with Nutrineal PD4 (Calcium Chloride Dihydrate) acetate, and there are no adequate and well controlled studies of Nutrineal PD4 (Calcium Chloride Dihydrate) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Nutrineal PD4 (Calcium Chloride Dihydrate) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Nutrineal PD4 (Calcium Chloride Dihydrate) 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. Nutrineal PD4 (Calcium Chloride Dihydrate) acetate treatment, as recommended, is not expected to harm a fetus if maternal Nutrineal PD4 (Calcium Chloride Dihydrate) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Nutrineal PD4 (Calcium Chloride Dihydrate) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Nutrineal PD4 Acetate Capsules contains Nutrineal PD4 (Calcium Chloride Dihydrate) acetate and is excreted in human milk. Human milk feeding by a mother receiving Nutrineal PD4 (Calcium Chloride Dihydrate) acetate is not expected to harm an infant, provided maternal serum Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Nutrineal PD4 (Calcium Chloride Dihydrate) acetate acts as a phosphate binder. Its chemical name is Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Nutrineal PD4 (Calcium Chloride Dihydrate), 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.

Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Nutrineal PD4 (Calcium Chloride Dihydrate) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Nutrineal PD4 (Calcium Chloride Dihydrate) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) acetate.

14 CLINICAL STUDIES

Effectiveness of Nutrineal PD4 (Calcium Chloride Dihydrate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Nutrineal PD4 (Calcium Chloride Dihydrate) 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


Nutrineal PD4 (Calcium Chloride Dihydrate) (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 Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) acetate is shown in the Table 3.


* ANOVA of Nutrineal PD4 (Calcium Chloride Dihydrate) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Nutrineal PD4 (Calcium Chloride Dihydrate) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Nutrineal PD4 (Calcium Chloride Dihydrate) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Nutrineal PD4 (Calcium Chloride Dihydrate) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Nutrineal PD4 (Calcium Chloride Dihydrate) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Nutrineal PD4 (Calcium Chloride Dihydrate) 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 Nutrineal PD4 (Calcium Chloride Dihydrate) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Glycine:


INDICATIONS AND USAGE

1.5% Nutrineal PD4 (Glycine) Irrigation, USP is indicated for use as irrigating fluid during transurethral prostatic resection and other transurethral surgical procedures.

CONTRAINDICATIONS

NOT FOR INJECTION BY USUAL PARENTERAL ROUTES.

Do not use in patients with anuria.

WARNINGS

FOR UROLOGIC IRRIGATION ONLY.

Solutions for urologic irrigation must be used with caution in patients with severe cardiopulmonary or renal dysfunction. Irrigating fluids used during transurethral prostatectomy have been demonstrated to enter the systemic circulation in relatively large volumes. Thus, Nutrineal PD4 (Glycine) irrigating solution must be regarded as a systemic drug. Absorption of large amounts of fluids containing Nutrineal PD4 (Glycine) may significantly alter cardiopulmonary and renal dynamics.

Do not heat container over 66°C (150°F).

PRECAUTIONS

Cardiovascular status, especially of the patient with cardiac disease, should be carefully observed before and during transurethral resection of the prostate when using Nutrineal PD4 (Glycine) irrigating solution, because the quantity of fluid absorbed into the systemic circulation by opened prostatic veins may produce significant expansion of the extracellular fluid and lead to fulminating congestive heart failure. Shift of sodium free intracellular fluid into the extracellular compartment following systemic absorption of solution may lower serum sodium concentration and aggravate pre-existing hyponatremia.

Care should be exercised if impaired liver function is known or suspected. Under such conditions, ammonia resulting from metabolism of Nutrineal PD4 (Glycine) may accumulate in the blood.

Aseptic technique is essential with the use of sterile solutions for irrigation. The administration set should be attached promptly. Unused portions should be discarded and a fresh container of appropriate size used for the start-up of each cycle or repeat procedure.

Do not administer unless solution is clear, seal is intact and container is undamaged. Discard unused portion.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with Nutrineal PD4 (Glycine) Irrigation, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

Nursing Mothers: Caution should be exercised when Nutrineal PD4 (Glycine) Irrigation, USP is administered to a nursing woman.

Pregnancy: Teratogenic Effects.

Pregnancy Category C. Animal reproduction studies have not been conducted with Nutrineal PD4 (Glycine) Irrigation, USP. It is also not known whether Nutrineal PD4 (Glycine) Irrigation, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Nutrineal PD4 (Glycine) Irrigation, USP should be given to a pregnant woman only if clearly needed.

Pediatric Use: The safety and effectiveness of Nutrineal PD4 (Glycine) Irrigation have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use.

ADVERSE REACTIONS

Adverse reactions may result from intravascular absorption of Nutrineal PD4 (Glycine). Large intravenous doses of Nutrineal PD4 (Glycine) are known to cause salivation, nausea and lightheadedness. Other consequences of absorption of urologic irrigating solutions include fluid and electrolyte disturbances such as acidosis, electrolyte loss, marked diuresis, urinary retention, edema, dryness of mouth, thirst, dehydration, coma from hyponatremia, secondary hyponatremia due to fluid overload, and hyper- ammonemia with resultant coma and/or encephalopathy; cardiovascular disorders such as hypotension, tachycardia, angina-like pains; pulmonary disorders such as pulmonary congestion; and other general reactions such as blurred vision, convulsions, nausea, vomiting, rhinitis, chills, vertigo, backache, transient blindness and urticaria. Allergic reactions from Nutrineal PD4 (Glycine) are unknown or exceedingly rare.

Should any adverse reaction occur, discontinue the irrigant, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.

OVERDOSAGE

In the event of overhydration or solute overload, re-evaluate the patient and institute appropriate corrective measures. See WARNINGS, PRECAUTIONS and ADVERSE REACTIONS.

DOSAGE AND ADMINISTRATION

1.5% Nutrineal PD4 (Glycine) Irrigation, USP should be administered only by transurethral instillation with appropriate urologic instrumentation. A disposable irrigation set should be used. The total volume of solution used for irrigation is solely at the discretion of the surgeon.

Height of container(s) above the operating table in excess of 60 cm (approx. 2 ft.) has been reported to increase intravascular absorption of the irrigating fluid.

Drug Interactions

Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution container permits. See PRECAUTIONS.

HOW SUPPLIED

1.5% Nutrineal PD4 (Glycine) Irrigation, USP is supplied in single-dose 3000 mL flexible irrigation container ( List No. 7974).

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. Store at 20 to 25°C (68 to 77°F).

Revised: October 2004

©Hospira 2004 EN-0577 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

IM-1453

iv bag ndc 0409-7974-08

2

HDPE

TO OPEN TEAR AT NOTCH

DO NOT REMOVE FROM OVERWRAP UNTIL READY FOR USE. AFTER REMOVING

THE OVERWRAP, CHECK FOR MINUTE LEAKS BY SQUEEZING CONTAINER FIRMLY.

IF LEAKS ARE FOUND, DISCARD SOLUTION AS STERILITY MAY BE IMPAIRED.

RECOMMENDED STORAGE: ROOM TEMPERATURE (25°C). AVOID EXCESSIVE

HEAT. PROTECT FROM FREEZING. SEE INSERT.

98-4321-R14-3/98

L-Alanine:


A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system.

Indication: Used for protein synthesis.

Is an important source of energy for muscle tissue, the brain and central nervous system; strengthens the immune system by producing antibodies; helps in the metabolism of sugars and organic acids.

L-Arginine:


An essential amino acid that is physiologically active in the L-form.

Indication: Used for nutritional supplementation, also for treating dietary shortage or imbalance.

Studies have shown that is has improved immune responses to bacteria, viruses and tumor cells; promotes wound healing and regeneration of the liver; causes the release of growth hormones; considered crucial for optimal muscle growth and tissue repair.

L-Histidine:


An essential amino acid that is required for the production of histamine.

Indication: The actions of supplemental Nutrineal PD4 (L-Histidine) are entirely unclear. It may have some immunomodulatory as well as antioxidant activity. Nutrineal PD4 (L-Histidine) may be indicated for use in some with rheumatoid arthritis. It is not indicated for treatment of anemia or uremia or for lowering serum cholesterol.

Is found abundantly in hemoglobin; has been used in the treatment of rheumatoid arthritis, allergic diseases, ulcers and anemia. A deficiency can cause poor hearing.

L-Isoleucine:


An essential branched-chain aliphatic amino acid found in many proteins. It is an isomer of leucine. It is important in hemoglobin synthesis and regulation of blood sugar and energy levels.

Indication: The branched-chain amino acids may have antihepatic encephalopathy activity in some. They may also have anticatabolic and antitardive dyskinesia activity.

They provide ingredients for the manufacturing of other essential biochemical components in the body, some of which are utilized for the production of energy, stimulants to the upper brain and helping you to be more alert.

L-Leucine:


An essential branched-chain amino acid important for hemoglobin formation.

Indication: Indicated to assist in the prevention of the breakdown of muscle proteins that sometimes occur after trauma or severe stress.

An essential amino acid. (Claim) Leucine helps with the regulation of blood-sugar levels, the growth and repair of muscle tissue (such as bones, skin and muscles), growth hormone production, wound healing as well as energy regulation. It can assist to prevent the breakdown of muscle proteins that sometimes occur after trauma or severe stress. It may also be beneficial for individuals with phenylketonuria - a condition in which the body cannot metabolize the amino acid phenylalanine

L-Lysine Hydrochloride:


Nutrineal PD4 (L-Lysine Hydrochloride) (abbreviated as Lys or K) is an О±-amino acid with the chemical formula HO2CCH(CH2)4NH2. This amino acid is an essential amino acid, which means that humans cannot synthesize it. Its codons are AAA and AAG.L-Lysine is a base, as are arginine and histidine. The Оµ-amino group often participates in hydrogen bonding and as a general base in catalysis. Common posttranslational modifications include methylation of the Оµ-amino group, giving methyl-, dimethyl-, and trimethyllysine. The latter occurs in calmodulin. Other posttranslational modifications include acetylation. Collagen contains hydroxylysine which is derived from lysine by lysyl hydroxylase. O-Glycosylation of lysine residues in the endoplasmic reticulum or Golgi apparatus is used to mark certain proteins for secretion from the cell.

Indication: Supplemental Nutrineal PD4 (L-Lysine Hydrochloride) has putative anti-herpes simplex virus activity. There is preliminary research suggesting that it may have some anti-osteoporotic activity.

Insures the adequate absorption of calcium; helps form collagen ( which makes up bone cartilage & connective tissues); aids in the production of antibodies, hormones & enzymes. Recent studies have shown that Lysine may be effective against herpes by improving the balance of nutrients that reduce viral growth. A deficiency may result in tiredness, inability to concentrate, irritability, bloodshot eyes, retarded growth, hair loss, anemia & reproductive problems.

L-Methionine:


A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals.

Indication: Used for protein synthesis including the formation of SAMe, L-homocysteine, L-cysteine, taurine, and sulfate.

Nutrineal PD4 (L-Methionine) is a principle supplier of sulfur which prevents disorders of the hair, skin and nails; helps lower cholesterol levels by increasing the liver's production of lecithin; reduces liver fat and protects the kidneys; a natural chelating agent for heavy metals; regulates the formation of ammonia and creates ammonia-free urine which reduces bladder irritation; influences hair follicles and promotes hair growth. Nutrineal PD4 (L-Methionine) may protect against the toxic effects of hepatotoxins, such as acetaminophen. Methionine may have antioxidant activity.

L-Phenylalanine:


An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine.

Indication: Nutrineal PD4 (L-Phenylalanine) may be helpful in some with depression. It may also be useful in the treatment of vitiligo. There is some evidence that Nutrineal PD4 (L-Phenylalanine) may exacerbate tardive dyskinesia in some schizophrenic patients and in some who have used neuroleptic drugs.

Used by the brain to produce Norepinephrine, a chemical that transmits signals between nerve cells and the brain; keeps you awake and alert; reduces hunger pains; functions as an antidepressant and helps improve memory.

L-Proline:


A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons.

Indication: Nutrineal PD4 (L-Proline) is extremely important for the proper functioning of joints and tendons and also helps maintain and strengthen heart muscles.

Nutrineal PD4 (L-Proline) is a major amino acid found in cartilage and is important for maintaining youthful skin as well as repair of muscle, connective tissue and skin damage. It is also essential for the immune system, and for necessary balance of this formula. It is an essential component of collagen and is important for proper functioning of joints and tendons. Nutrineal PD4 (L-Proline) is extremely important for the proper functioning of joints and tendons. Helps maintain and strengthen heart muscles.

L-Serine:


A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines; pyrimidines; and other amino acids.

Indication: Used as a natural moisturizing agent in some cosmetics and skin care products.

Serine is classified as a nutritionally non-essential amino acid. Serine is critical for the production of the body's proteins, enzymes and muscle tissue. Serine is needed for the proper metabolism of fats and fatty acids. It also helps in the production of antibodies. Serine is used as a natural moisturizing agent in some cosmetics and skin care products. The main source of essential amino acids is from the diet, non-essential amino acids are normally synthesize by humans and other mammals from common intermediates.

L-Threonine:


An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins.

Indication: Nutrineal PD4 (L-Threonine) makes up collagen, elastin, and enamel protein. It aids proper fat metabolism in the liver, helps the digestive and intestinal tracts function more smoothly, and assists in metabolism and assimilation.

Nutrineal PD4 (L-Threonine) is an essential amino acid that helps to maintain the proper protein balance in the body. It is important for the formation of collagen, elastin, and tooth enamel, and aids liver and lipotropic function when combined with aspartic acid and methionine.

L-Tryptophan:


An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor of indole alkaloids in plants. It is a precursor of serotonin (hence its use as an antidepressant and sleep aid). It can be a precursor to niacin, albeit inefficiently, in mammals.

Indication: Tryptophan may be useful in increasing serotonin production, promoting healthy sleep, managing depression by enhancing mental and emotional well-being, managing pain tolerance, and managing weight.

Tryptophan is critical for the production of the body's proteins, enzymes and muscle tissue. It is also essential for the production of niacin, the synthesis of the neurotransmitter serotonin and melatonin. Tryptophan supplements can be used as natural relaxants to help relieve insomnia. Tryptophan can also reduce anxiety and depression and has been shown to reduce the intensity of migraine headaches. Other promising indications include the relief of chronic pain, reduction of impulsivity or mania and the treatment of obsessive or compulsive disorders. Tryptophan also appears to help the immune system and can reduce the risk of cardiac spasms. Tryptophan deficiencies may lead to coronary artery spasms. Tryptophan is used as an essential nutrient in infant formulas and intravenous feeding. Tryptophan is marketed as a prescription drug (Tryptan) for those who do not seem to respond well to conventional antidepressants. It may also be used to treat those afflicted with seasonal affective disorder (a winter-onset depression). Tryptopan serves as the precursor for the synthesis of serotonin (5-hydroxytryptamine, 5-HT) and melatonin (N-acetyl-5-methoxytryptamine).

L-Tyrosine:


A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin.

Indication: Tyrosine is claimed to act as an effective antidepressant, however results are mixed. Tyrosine has also been claimed to reduce stress and combat narcolepsy and chronic fatigue, however these claims have been refuted by some studies.

Tyrosine is a nonessential amino acid synthesized in the body from phenylalanine. Tyrosine is critical for the production of the body's proteins, enzymes and muscle tissue. Tyrosine is a precursor to the neurotransmitters norepinephrine and dopamine. It can act as a mood elevator and an anti-depressant. It may improve memory and increase mental alertness. Tyrosine aids in the production of melanin and plays a critical role in the production of thyroxin (thyroid hormones). Tyrosine deficiencies are manifested by hypothyroidism, low blood pressure and low body temperature. Supplemental tyrosine has been used to reduce stress and combat narcolepsy and chronic fatigue.

L-Valine:


A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway.

Indication: Promotes mental vigor, muscle coordination, and calm emotions. May also be of use in a minority of patients with hepatic encephalopathy and in some with phenylketonuria.

Nutrineal PD4 (L-Valine) is a branched-chain essential amino acid (BCAA) that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. Valine is one of three branched-chain amino acids (the others are leucine and isoleucine) that enhance energy, increase endurance, and aid in muscle tissue recovery and repair. This group also lowers elevated blood sugar levels and increases growth hormone production. Supplemental valine should always be combined with isoleucine and leucine at a respective milligram ratio of 2:1:2. It is an essential amino acid found in proteins; important for optimal growth in infants and for growth in children and nitrogen balance in adults. The lack of Nutrineal PD4 (L-Valine) may influence the growth of body, cause neuropathic obstacle, anaemia. It has wide applications in the field of pharmaceutical and food industry.

Sodium Chloride:


1 INDICATIONS AND USAGE

Nutrineal PD4 nitrite is indicated for sequential use with Nutrineal PD4 (Sodium Chloride) 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

Nutrineal PD4 (Sodium Chloride) Nitrite Injection is indicated for sequential use with Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 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, Nutrineal PD4 (Sodium Chloride) Nitrite Injection and Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) thiosulfate, simultaneously with Nutrineal PD4 (Sodium Chloride) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Nutrineal PD4 (Sodium Chloride) thiosulfate, with Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 Nitrite and Nutrineal PD4 (Sodium Chloride) Thiosulfate
Adults
  • Nutrineal PD4 (Sodium Chloride) Nitrite -10 mL of Nutrineal PD4 (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute
  • Nutrineal PD4 (Sodium Chloride) Thiosulfate - 50 mL of Nutrineal PD4 (Sodium Chloride) thiosulfate immediately following administration of Nutrineal PD4 (Sodium Chloride) nitrite.
Children
  • Nutrineal PD4 (Sodium Chloride) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Nutrineal PD4 (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Nutrineal PD4 (Sodium Chloride) nitrite and Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite, followed by Nutrineal PD4 (Sodium Chloride) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Nutrineal PD4 (Sodium Chloride) nitrite and Nutrineal PD4 (Sodium Chloride) thiosulfate.

Nutrineal PD4 (Sodium Chloride) nitrite injection and Nutrineal PD4 (Sodium Chloride) 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. Nutrineal PD4 (Sodium Chloride) nitrite should be administered first, followed immediately by Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) Nitrite and Nutrineal PD4 (Sodium Chloride) Thiosulfate
Adults
  • Nutrineal PD4 (Sodium Chloride) Nitrite -10 mL of Nutrineal PD4 (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute
  • Nutrineal PD4 (Sodium Chloride) Thiosulfate - 50 mL of Nutrineal PD4 (Sodium Chloride) thiosulfate immediately following administration of Nutrineal PD4 (Sodium Chloride) nitrite.
Children
  • Nutrineal PD4 (Sodium Chloride) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Nutrineal PD4 (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Nutrineal PD4 (Sodium Chloride) nitrite and Nutrineal PD4 (Sodium Chloride) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 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 Nutrineal PD4 (Sodium Chloride) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Nutrineal PD4 (Sodium Chloride) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Nutrineal PD4 (Sodium Chloride) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Nutrineal PD4 (Sodium Chloride) thiosulfate and Nutrineal PD4 (Sodium Chloride) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Nutrineal PD4 (Sodium Chloride) Nitrite Injection consists of:

  • One vial of Nutrineal PD4 (Sodium Chloride) 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: Nutrineal PD4 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 Nutrineal PD4 (Sodium Chloride) 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. Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Nutrineal PD4 (Sodium Chloride) nitrite whenever possible. When Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite administered to an adult. Nutrineal PD4 (Sodium Chloride) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Nutrineal PD4 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 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 Nutrineal PD4 (Sodium Chloride) nitrite.

5.7 Use with Other Drugs

Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite.

The medical literature has reported the following adverse events in association with Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Nutrineal PD4 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. Nutrineal PD4 (Sodium Chloride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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, Nutrineal PD4 (Sodium Chloride) 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, Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Nutrineal PD4 (Sodium Chloride) 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, Nutrineal PD4 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 Nutrineal PD4 (Sodium Chloride) nitrite is excreted in human milk. Because Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Nutrineal PD4 (Sodium Chloride) nitrite. In studies conducted with Long-Evans rats, Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 nitrite in conjunction with Nutrineal PD4 (Sodium Chloride) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Nutrineal PD4 (Sodium Chloride) 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.

Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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

Nutrineal PD4 (Sodium Chloride) 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

Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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

Nutrineal PD4 (Sodium Chloride) nitrite has the chemical name nitrous acid Nutrineal PD4 (Sodium Chloride) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:

Structure of Nutrineal PD4 (Sodium Chloride) Nitrite

Nutrineal PD4 (Sodium Chloride) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Nutrineal PD4 (Sodium Chloride) nitrite injection.

Nutrineal PD4 (Sodium Chloride) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Nutrineal PD4 (Sodium Chloride) nitrite in 10 mL solution (30 mg/mL). Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 nitrite and Nutrineal PD4 (Sodium Chloride) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Nutrineal PD4 (Sodium Chloride) Nitrite

Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite. It has been suggested that Nutrineal PD4 (Sodium Chloride) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Nutrineal PD4 (Sodium Chloride) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Nutrineal PD4 (Sodium Chloride) 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. Nutrineal PD4 (Sodium Chloride) 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

Nutrineal PD4 (Sodium Chloride) Nitrite

When 4 mg/kg Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Nutrineal PD4 (Sodium Chloride) Nitrite

Nutrineal PD4 (Sodium Chloride) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Nutrineal PD4 (Sodium Chloride) nitrite in humans have not been well studied. It has been reported that approximately 40% of Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite and Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Nutrineal PD4 (Sodium Chloride) 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. Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Nutrineal PD4 (Sodium Chloride) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Nutrineal PD4 (Sodium Chloride) 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. Nutrineal PD4 (Sodium Chloride) 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. Nutrineal PD4 (Sodium Chloride) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Nutrineal PD4 (Sodium Chloride) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite and Nutrineal PD4 (Sodium Chloride) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Nutrineal PD4 (Sodium Chloride) nitrite or 1 g/kg Nutrineal PD4 (Sodium Chloride) thiosulfate alone or in sequence immediately after subcutaneous injection of Nutrineal PD4 (Sodium Chloride) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Nutrineal PD4 (Sodium Chloride) nitrite and/or 0.5 g/kg Nutrineal PD4 (Sodium Chloride) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Nutrineal PD4 (Sodium Chloride) cyanide required to cause death, and when administered together, Nutrineal PD4 (Sodium Chloride) nitrite and Nutrineal PD4 (Sodium Chloride) thiosulfate resulted in a synergistic effect in raising the lethal dose of Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) nitrite and Nutrineal PD4 (Sodium Chloride) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Nutrineal PD4 (Sodium Chloride) nitrite and Nutrineal PD4 (Sodium Chloride) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Nutrineal PD4 (Sodium Chloride) nitrite, with or without Nutrineal PD4 (Sodium Chloride) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) thiosulfate report its use in conjunction with Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) 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 Nutrineal PD4 (Sodium Chloride) Nitrite carton (NDC 60267-311-10) consists of the following:

  • One 10 mL glass vial of Nutrineal PD4 (Sodium Chloride) nitrite injection 30 mg/mL (containing 300 mg of Nutrineal PD4 (Sodium Chloride) 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: Nutrineal PD4 (Sodium Chloride) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Nutrineal PD4 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

Nutrineal PD4 (Sodium Chloride) 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

Nutrineal PD4 (Sodium Chloride) 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

Sodium Lactate:


1 INDICATIONS AND USAGE

Nutrineal PD4 nitrite is indicated for sequential use with Nutrineal PD4 (Sodium Lactate) 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

Nutrineal PD4 (Sodium Lactate) Nitrite Injection is indicated for sequential use with Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 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, Nutrineal PD4 (Sodium Lactate) Nitrite Injection and Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) thiosulfate, simultaneously with Nutrineal PD4 (Sodium Lactate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Nutrineal PD4 (Sodium Lactate) thiosulfate, with Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 Nitrite and Nutrineal PD4 (Sodium Lactate) Thiosulfate
Adults
  • Nutrineal PD4 (Sodium Lactate) Nitrite -10 mL of Nutrineal PD4 (Sodium Lactate) nitrite at the rate of 2.5 to 5 mL/minute
  • Nutrineal PD4 (Sodium Lactate) Thiosulfate - 50 mL of Nutrineal PD4 (Sodium Lactate) thiosulfate immediately following administration of Nutrineal PD4 (Sodium Lactate) nitrite.
Children
  • Nutrineal PD4 (Sodium Lactate) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Nutrineal PD4 (Sodium Lactate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Nutrineal PD4 (Sodium Lactate) nitrite and Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite, followed by Nutrineal PD4 (Sodium Lactate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Nutrineal PD4 (Sodium Lactate) nitrite and Nutrineal PD4 (Sodium Lactate) thiosulfate.

Nutrineal PD4 (Sodium Lactate) nitrite injection and Nutrineal PD4 (Sodium Lactate) 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. Nutrineal PD4 (Sodium Lactate) nitrite should be administered first, followed immediately by Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) Nitrite and Nutrineal PD4 (Sodium Lactate) Thiosulfate
Adults
  • Nutrineal PD4 (Sodium Lactate) Nitrite -10 mL of Nutrineal PD4 (Sodium Lactate) nitrite at the rate of 2.5 to 5 mL/minute
  • Nutrineal PD4 (Sodium Lactate) Thiosulfate - 50 mL of Nutrineal PD4 (Sodium Lactate) thiosulfate immediately following administration of Nutrineal PD4 (Sodium Lactate) nitrite.
Children
  • Nutrineal PD4 (Sodium Lactate) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Nutrineal PD4 (Sodium Lactate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Nutrineal PD4 (Sodium Lactate) nitrite and Nutrineal PD4 (Sodium Lactate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 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 Nutrineal PD4 (Sodium Lactate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Nutrineal PD4 (Sodium Lactate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Nutrineal PD4 (Sodium Lactate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Nutrineal PD4 (Sodium Lactate) thiosulfate and Nutrineal PD4 (Sodium Lactate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Nutrineal PD4 (Sodium Lactate) Nitrite Injection consists of:

  • One vial of Nutrineal PD4 (Sodium Lactate) 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: Nutrineal PD4 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 Nutrineal PD4 (Sodium Lactate) 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. Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Nutrineal PD4 (Sodium Lactate) nitrite whenever possible. When Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite administered to an adult. Nutrineal PD4 (Sodium Lactate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Nutrineal PD4 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 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 Nutrineal PD4 (Sodium Lactate) nitrite.

5.7 Use with Other Drugs

Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite.

The medical literature has reported the following adverse events in association with Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Nutrineal PD4 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. Nutrineal PD4 (Sodium Lactate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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, Nutrineal PD4 (Sodium Lactate) 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, Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Nutrineal PD4 (Sodium Lactate) 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, Nutrineal PD4 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 Nutrineal PD4 (Sodium Lactate) nitrite is excreted in human milk. Because Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Nutrineal PD4 (Sodium Lactate) nitrite. In studies conducted with Long-Evans rats, Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 nitrite in conjunction with Nutrineal PD4 (Sodium Lactate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Nutrineal PD4 (Sodium Lactate) 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.

Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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

Nutrineal PD4 (Sodium Lactate) 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

Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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

Nutrineal PD4 (Sodium Lactate) nitrite has the chemical name nitrous acid Nutrineal PD4 (Sodium Lactate) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:

Structure of Nutrineal PD4 (Sodium Lactate) Nitrite

Nutrineal PD4 (Sodium Lactate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Nutrineal PD4 (Sodium Lactate) nitrite injection.

Nutrineal PD4 (Sodium Lactate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Nutrineal PD4 (Sodium Lactate) nitrite in 10 mL solution (30 mg/mL). Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 nitrite and Nutrineal PD4 (Sodium Lactate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Nutrineal PD4 (Sodium Lactate) Nitrite

Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite. It has been suggested that Nutrineal PD4 (Sodium Lactate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Nutrineal PD4 (Sodium Lactate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Nutrineal PD4 (Sodium Lactate) 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. Nutrineal PD4 (Sodium Lactate) 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

Nutrineal PD4 (Sodium Lactate) Nitrite

When 4 mg/kg Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Nutrineal PD4 (Sodium Lactate) Nitrite

Nutrineal PD4 (Sodium Lactate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Nutrineal PD4 (Sodium Lactate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite and Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Nutrineal PD4 (Sodium Lactate) 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. Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Nutrineal PD4 (Sodium Lactate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Nutrineal PD4 (Sodium Lactate) 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. Nutrineal PD4 (Sodium Lactate) 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. Nutrineal PD4 (Sodium Lactate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Nutrineal PD4 (Sodium Lactate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite and Nutrineal PD4 (Sodium Lactate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Nutrineal PD4 (Sodium Lactate) nitrite or 1 g/kg Nutrineal PD4 (Sodium Lactate) thiosulfate alone or in sequence immediately after subcutaneous injection of Nutrineal PD4 (Sodium Lactate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Nutrineal PD4 (Sodium Lactate) nitrite and/or 0.5 g/kg Nutrineal PD4 (Sodium Lactate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Nutrineal PD4 (Sodium Lactate) cyanide required to cause death, and when administered together, Nutrineal PD4 (Sodium Lactate) nitrite and Nutrineal PD4 (Sodium Lactate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) nitrite and Nutrineal PD4 (Sodium Lactate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Nutrineal PD4 (Sodium Lactate) nitrite and Nutrineal PD4 (Sodium Lactate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Nutrineal PD4 (Sodium Lactate) nitrite, with or without Nutrineal PD4 (Sodium Lactate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) thiosulfate report its use in conjunction with Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) 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 Nutrineal PD4 (Sodium Lactate) Nitrite carton (NDC 60267-311-10) consists of the following:

  • One 10 mL glass vial of Nutrineal PD4 (Sodium Lactate) nitrite injection 30 mg/mL (containing 300 mg of Nutrineal PD4 (Sodium Lactate) 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: Nutrineal PD4 (Sodium Lactate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Nutrineal PD4 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

Nutrineal PD4 (Sodium Lactate) 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

Nutrineal PD4 (Sodium Lactate) 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

Nutrineal PD4 pharmaceutical active ingredients containing related brand and generic drugs:

infoActive 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.


Nutrineal PD4 available forms, composition, doses:

infoForm 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.


Nutrineal PD4 destination | category:

infoDestination 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.


Nutrineal PD4 Anatomical Therapeutic Chemical codes:

infoA 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.


Nutrineal PD4 pharmaceutical companies:

infoPharmaceutical 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."NASAL SPA NATURAL SEA SALT (SODIUM CHLORIDE) SPRAY [NACUR HEALTHCARE LTD]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."GLYCINE IRRIGANT [HOSPIRA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."SODIUM LACTATE INJECTION, SOLUTION, CONCENTRATE [HOSPIRA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Nutrineal PD4?

Depending on the reaction of the Nutrineal PD4 after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Nutrineal PD4 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 Nutrineal PD4 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 Nutrineal PD4, 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 Nutrineal PD4 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. Arunabha Ray, MD Pharmacology

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