Celemin-5S

Arginine Hydrochloride:

• Celemin-5S (Arginine Hydrochloride) reviews

Nutritive Wound - Skin Cream

For Minor Cuts and Wounds

- Eases Discomfort

- Soothing Cream

CONTAINS:

Celemin-5S (Arginine Hydrochloride) Aminobenzoate 2.5% Patent # 5734080

In a cream base with Safflower Oil, Apricot Kernel Oil, Mixed Tocopherols, Glycerin, Coconut Oil, Borage Oil, Tea Tree Oil, Camphor, Thymine, Lecithin, Grapefruit Extract, Lemon Oil and Aloe Vera.

DIRECTIONS:

Apply topically as needed to superficial wounds and abrasions.

INDICATIONS FOR USE:

FelineAid can be used on minor cuts, abrasions and irritations as well as superficial wounds and skin lesions on cats.

CAUTIONS:

Avoid contact with eyes. If contact occurs, flush with copious amounts of water. If condition persists or worsens discontinue use.

Shake Well

Store at room temperature.

For Veterinary Use Only

Glycine:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Im-1453
• Celemin-5S (Glycine) reviews

INDICATIONS AND USAGE

1.5% Celemin-5S (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, Celemin-5S (Glycine) irrigating solution must be regarded as a systemic drug. Absorption of large amounts of fluids containing Celemin-5S (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 Celemin-5S (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 Celemin-5S (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 Celemin-5S (Glycine) Irrigation, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

Nursing Mothers: Caution should be exercised when Celemin-5S (Glycine) Irrigation, USP is administered to a nursing woman.

Pregnancy: Teratogenic Effects.

Pregnancy Category C. Animal reproduction studies have not been conducted with Celemin-5S (Glycine) Irrigation, USP. It is also not known whether Celemin-5S (Glycine) Irrigation, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Celemin-5S (Glycine) Irrigation, USP should be given to a pregnant woman only if clearly needed.

Pediatric Use: The safety and effectiveness of Celemin-5S (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 Celemin-5S (Glycine). Large intravenous doses of Celemin-5S (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 Celemin-5S (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% Celemin-5S (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% Celemin-5S (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:

• Celemin-5S (L-Alanine) reviews

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-Aspartic Acid:

• Celemin-5S (L-Aspartic Acid) reviews

One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter.

Indication: There is no support for the claim that aspartates are exercise performance enhancers, i.e. ergogenic aids.

L-aspartate is considered a non-essential amino acid, meaning that, under normal physiological conditions, sufficient amounts of the amino acid are synthesized in the body to meet the body's requirements. L-aspartate is formed by the transamination of the Krebs cycle intermediate oxaloacetate. The amino acid serves as a precursor for synthesis of proteins, oligopeptides, purines, pyrimidines, nucleic acids and L-arginine. L-aspartate is a glycogenic amino acid, and it can also promote energy production via its metabolism in the Krebs cycle. These latter activities were the rationale for the claim that supplemental aspartate has an anti-fatigue effect on skeletal muscle, a claim that was never confirmed.

L-Cysteine:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Dosage and administration
• Directions for proper use of pharmacy bulk package
• Recommended storage conditions after opening
• How supplied
• Celemin-5S (L-Cysteine) reviews

INDICATIONS AND USAGE

Celemin-5S (L-Cysteine) Hydrochloride Injection, USP is intended for use only after dilution as an additive to Crystalline Amino Acid Injections to meet the intravenous amino acid nutritional requirements of infants receiving total parenteral nutrition.

CONTRAINDICATIONS

This preparation should not be used in patients with hepatic coma or metabolic disorders involving impaired nitrogen utilization.

WARNINGS

Peripheral intravenous infusion of amino acids may induce a rise in blood urea nitrogen (BUN) especially in patients with impaired hepatic or renal function. Appropriate laboratory tests should be performed periodically and infusion discontinued if BUN levels exceed normal postprandial limits and continue to rise. It should be noted that a modest rise in BUN normally occurs as a result of increased protein intake.

Administration of amino acid solutions to a patient with hepatic insufficiency may result in serum amino acid imbalances, metabolic alkalosis, prerenal azotemia, hyperammonemia, stupor and coma.

Administration of amino acid solutions in the presence of impaired renal function may augment an increasing BUN, as does any protein dietary component.

Solutions containing sodium ion should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention.

Solutions which contain potassium ion should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present.

Solutions containing acetate ion should be used with great care in patients with metabolic or respiratory alkalosis. Acetate should be administered with great care in those conditions in which there is an increased level or an impaired utilization of this ion such as severe hepatic insufficiency.

Hyperammonemia is of special significance in infants, as it can result in mental retardation. Therefore it is essential that blood ammonia levels be measured frequently in infants.

Instances of asymptomatic hyperammonemia have been reported in patients without overt liver dysfunction. The mechanisms of this reaction are not clearly defined but may involve genetic defects and immature or subclinically impaired liver function.

Frequent Clinical Evaluation and Laboratory Determinations are Necessary for Proper Monitoring During Administration. Blood studies should include glucose, urea nitrogen, serum electrolytes, ammonia, cholesterol, acid-base balance, serum proteins, kidney and liver function tests, osmolarity and hemogram. White blood count and blood cultures are to be determined if indicated. Urinary osmolarity and glucose should be determined frequently.

Safe use during pregnancy has not been established, therefore, infusion of amino acids should be undertaken during pregnancy only when this is deemed essential to the patients' welfare, as judged by the physician.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration

PRECAUTIONS

Special care must be taken when administering hypertonic glucose to provide calories in diabetic or prediabetic patients.

Because of its antianabolic activity, concurrent administration of tetracycline may reduce the nitrogen sparing effects of infused amino acids.

Do not withdraw venous blood for blood chemistries through the peripheral infusion site, as interference with estimations of nitrogen containing substances may occur.

Intravenous feeding regimens which include amino acids should be used with caution in patients with a history of renal disease, pulmonary disease, or with cardiac insufficiency so as to avoid excessive fluid accumulation.

The effect of infusion of amino acids, without dextrose, upon carbohydrate metabolism of children is not known at this time.

Nitrogen intake should be carefully monitored in patients with impaired renal function. For long-term total nutrition, or if a patient has inadequate fat stores, it is essential to provide adequate exogenous calories concurrently with the amino acids. Concentrated dextrose solutions are an effective source of such calories. Such strongly hypertonic nutrient solutions should be administered through an indwelling intravenous catheter with the tip located in the superior vena cava.

ADVERSE REACTIONS

Local reactions consisting of a warm sensation, erythema, phlebitis and thrombosis at the infusion site have occurred with peripheral intravenous infusion of amino acids, particularly if the other substances, such as antibiotics, are also administered through the same site. In such cases the infusion site should be changed promptly to another vein. Use of large peripheral veins, inline filters, and slowing the rate of infusion may reduce the incidence of local venous irritation. Electrolyte additives should be spread throughout the day. Irritating additive medications may need to be injected at another venous site.

Generalized flushing, fever and nausea also have been reported during peripheral infusions of amino acid solutions.

Drug Abuse and Dependence

None known.

DOSAGE AND ADMINISTRATION

Celemin-5S (L-Cysteine) Hydrochloride Injection USP is intended for use only after dilution in Crystalline Amino Acid Injection. Each 0.5 gram of Celemin-5S (L-Cysteine) Hydrochloride Monohydrate should be combined aseptically with 12.5 grams of Crystalline Amino Acid Injection, such as that present in 250 mL of 5% Crystalline Amino Acid Injection. The admixture is then diluted with 250 mL of dextrose 50% or such lesser volume as indicated. Equal volumes of 5% Crystalline Amino Acid Injection and dextrose 50% produce a final solution which contains Crystalline Amino Acid Injection 2.5% in dextrose 25%, which is suitable for administration by central venous infusion. Administration of the final admixture should begin within one hour of mixing. Otherwise, the admixture should be refrigerated immediately and used within 24 hours of the time of mixing. For the recommended rate of administration, see the Crystalline Amino Acid Injection package insert.

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

DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE

The pharmacy bulk package is for use in a Pharmacy Admixture Service only.

Use of this product is restricted to a suitable work area, such as a laminar flow hood. Prior to entering the vial, remove the flip-off seal and cleanse the rubber closure with a suitable antiseptic agent.

The container closure may be penetrated only one time, utilizing a suitable sterile transfer device or dispensing set which allows measured distribution of the contents. The date and time the vial was initially opened should be recorded in the space provided on the label. Transfer individual doses(s) to appropriate intravenous infusion solutions. Use of a syringe with needle is not recommended. Multiple entries increase the potential of microbial and particulate contamination.

The withdrawal of container contents should be accomplished without delay using aseptic technique. However, should this not be possible, a maximum time of 4 hours from initial closure entry is permitted to complete fluid transfer operations.

RECOMMENDED STORAGE CONDITIONS AFTER OPENING

Keep under laminar flow hood at room temperature. Any unused portion of the vial must be discarded within 4 hours after initial entry.

HOW SUPPLIED

Celemin-5S (L-Cysteine) Hydrochloride Injection, USP (50 mg/mL) is supplied as follows:

NDC Number	Volume
66758-005-01	50 mL
66758-005-02	5 × 50 mL

Also available as:

NDC Number	Volume
66758-004-01	10 mL
66758-004-02	10 × 10 mL

Store at controlled room temperature 15°-30°C (59°-86°F) Do not freeze.

For Sandoz Inc. Customer Service, call 1-800-525-8747

Rx only

Manufactured for:

SANDOZ

Princeton, NJ 08540

Revised: November 2009

L-028-00

SANDOZ

Rx only NDC 66758-005-01

Celemin-5S (L-Cysteine)

Hydrochloride Injection, USP

PHARMACY BULK PACKAGE

NOT FOR DIRECT INFUSION

50 mg/mL

For IV Use Only After Dilution

Do Not Dispense As A Unit

50 mL

L-018-00

PHARMACY BULK PACKAGE

SANDOZ

5 × 50 mL Vials NDC 66758-005-02

Celemin-5S (L-Cysteine) Hydrochloride

Injection, USP

50 mg/mL

Pharmacy Bulk Package

Not For Direct Infusion

For IV Use Only After Dilution

Rx only

vial carton

L-Glutamic Acid:

• Celemin-5S (L-Glutamic Acid) reviews

A peptide that is a homopolymer of glutamic acid.

Indication: Considered to be nature's "Brain food" by improving mental capacities; helps speed the healing of ulcers; gives a "lift" from fatigue; helps control alcoholism, schizophrenia and the craving for sugar.

In addition to being one of the building blocks in protein synthesis, it is the most widespread neurotransmitter in brain function, as an excitatory neurotransmitter and as a precursor for the synthesis of GABA in GABAergic neurons.

L-Histidine Hydrochloride:

• Celemin-5S (L-Histidine Hydrochloride) reviews

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

Indication: The actions of supplemental Celemin-5S (L-Histidine Hydrochloride) are entirely unclear. It may have some immunomodulatory as well as antioxidant activity. Celemin-5S (L-Histidine Hydrochloride) 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:

• Celemin-5S (L-Isoleucine) reviews

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:

• Celemin-5S (L-Leucine) reviews

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 Monohydrochloride:

• Celemin-5S (L-Lysine Monohydrochloride) reviews

Celemin-5S (L-Lysine Monohydrochloride) (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 Celemin-5S (L-Lysine Monohydrochloride) 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:

• Celemin-5S (L-Methionine) reviews

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.

Celemin-5S (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. Celemin-5S (L-Methionine) may protect against the toxic effects of hepatotoxins, such as acetaminophen. Methionine may have antioxidant activity.

L-Phenylalanine:

• Celemin-5S (L-Phenylalanine) reviews

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

Indication: Celemin-5S (L-Phenylalanine) may be helpful in some with depression. It may also be useful in the treatment of vitiligo. There is some evidence that Celemin-5S (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:

• Celemin-5S (L-Proline) reviews

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: Celemin-5S (L-Proline) is extremely important for the proper functioning of joints and tendons and also helps maintain and strengthen heart muscles.

Celemin-5S (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. Celemin-5S (L-Proline) is extremely important for the proper functioning of joints and tendons. Helps maintain and strengthen heart muscles.

L-Serine:

• Celemin-5S (L-Serine) reviews

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:

• Celemin-5S (L-Threonine) reviews

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: Celemin-5S (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.

Celemin-5S (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:

• Celemin-5S (L-Tryptophan) reviews

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-Valine:

• Celemin-5S (L-Valine) reviews

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.

Celemin-5S (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 Celemin-5S (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:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Celemin-5S (Sodium) reviews

1 INDICATIONS AND USAGE

Celemin-5S nitrite is indicated for sequential use with Celemin-5S (Sodium) 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

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

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Celemin-5S (Sodium) nitrite and Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite, followed by Celemin-5S (Sodium) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Celemin-5S (Sodium) nitrite and Celemin-5S (Sodium) thiosulfate.

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

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Celemin-5S (Sodium) nitrite and Celemin-5S (Sodium) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Celemin-5S (Sodium) 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 Celemin-5S 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 Celemin-5S (Sodium) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Celemin-5S (Sodium) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Celemin-5S (Sodium) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Celemin-5S (Sodium) thiosulfate and Celemin-5S (Sodium) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Celemin-5S (Sodium) Nitrite Injection consists of:

• One vial of Celemin-5S (Sodium) 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: Celemin-5S 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 Celemin-5S (Sodium) 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. Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Celemin-5S (Sodium) nitrite whenever possible. When Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite administered to an adult. Celemin-5S (Sodium) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Celemin-5S 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 Celemin-5S (Sodium) 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 Celemin-5S 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 Celemin-5S (Sodium) nitrite.

5.7 Use with Other Drugs

Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite.

The medical literature has reported the following adverse events in association with Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Celemin-5S 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. Celemin-5S (Sodium) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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, Celemin-5S (Sodium) 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, Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Celemin-5S (Sodium) 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, Celemin-5S 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 Celemin-5S (Sodium) nitrite is excreted in human milk. Because Celemin-5S (Sodium) 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 Celemin-5S (Sodium) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Celemin-5S (Sodium) nitrite. In studies conducted with Long-Evans rats, Celemin-5S (Sodium) 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 Celemin-5S nitrite in conjunction with Celemin-5S (Sodium) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Celemin-5S (Sodium) 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.

Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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

Celemin-5S (Sodium) 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

Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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

Celemin-5S (Sodium) nitrite has the chemical name nitrous acid Celemin-5S (Sodium) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Celemin-5S (Sodium) Nitrite

Celemin-5S (Sodium) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Celemin-5S (Sodium) nitrite injection.

Celemin-5S (Sodium) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Celemin-5S (Sodium) nitrite in 10 mL solution (30 mg/mL). Celemin-5S (Sodium) 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 Celemin-5S nitrite and Celemin-5S (Sodium) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Celemin-5S (Sodium) Nitrite

Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite. It has been suggested that Celemin-5S (Sodium) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Celemin-5S (Sodium) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Celemin-5S (Sodium) 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. Celemin-5S (Sodium) 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

Celemin-5S (Sodium) Nitrite

When 4 mg/kg Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Celemin-5S (Sodium) Nitrite

Celemin-5S (Sodium) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Celemin-5S (Sodium) nitrite in humans have not been well studied. It has been reported that approximately 40% of Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite and Celemin-5S (Sodium) 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 Celemin-5S nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Celemin-5S (Sodium) 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. Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Celemin-5S (Sodium) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Celemin-5S (Sodium) 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. Celemin-5S (Sodium) 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. Celemin-5S (Sodium) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Celemin-5S (Sodium) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite and Celemin-5S (Sodium) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Celemin-5S (Sodium) nitrite or 1 g/kg Celemin-5S (Sodium) thiosulfate alone or in sequence immediately after subcutaneous injection of Celemin-5S (Sodium) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Celemin-5S (Sodium) nitrite and/or 0.5 g/kg Celemin-5S (Sodium) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Celemin-5S (Sodium) cyanide required to cause death, and when administered together, Celemin-5S (Sodium) nitrite and Celemin-5S (Sodium) thiosulfate resulted in a synergistic effect in raising the lethal dose of Celemin-5S (Sodium) 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 Celemin-5S (Sodium) nitrite and Celemin-5S (Sodium) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Celemin-5S (Sodium) nitrite and Celemin-5S (Sodium) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Celemin-5S (Sodium) nitrite, with or without Celemin-5S (Sodium) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Celemin-5S (Sodium) 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 Celemin-5S (Sodium) thiosulfate report its use in conjunction with Celemin-5S (Sodium) 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 Celemin-5S (Sodium) 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 Celemin-5S (Sodium) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Celemin-5S (Sodium) nitrite injection 30 mg/mL (containing 300 mg of Celemin-5S (Sodium) 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: Celemin-5S (Sodium) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Celemin-5S 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

Celemin-5S (Sodium) 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

Celemin-5S (Sodium) 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

Sorbitol:

• Active ingredient (in each tablespoonful=15 ml )
• Purpose
• Uses
• Warnings
• Directions
• Other information
• Inactive ingredient
• Celemin-5S (Sorbitol) reviews

Active ingredient

Celemin-5S (Sorbitol) 13.5g

Purpose

Laxative

Uses

• relieves occasional constipation and irregularity
• generally produces bowel movement in 1/4 to 1 hour when used rectally
• as a pharmaceutical aide (sweetner)
• for other uses, as your doctor
  

Warnings

Do not use

• when abdominal pain, nausea, or vomiting are present
• for more than one week unless directed by a doctor
  

Ask a doctor before use if you

• are taking mineral oil
• have noticed a sudden change in bowel habits that lasts over 2 weeks
  

Stop use and ask a doctor if you have rectal bleeding or no bowel movement after using this product. These could be signs of a serious condition.

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children. In case of overdose, get medical help or contact a

Poison Control Center right away.

Directions

- do not exceed recommended dose

Age	Dose
adults and children 12 years and over	For rectal use only. Enema dosage is 120 mL of a 25 to 30% w/v solution (1 part of this product with 2.3 parts water) in a single daily dose as needed, or as directed by your doctor.
children under 12 years	Ask a doctor.

Other information

- store at room temperature 15-30C (59-86F)

- below 59F cloudiness and thickening may occur; warming will restore clarity and fluidity without affecting product quality

- do not freeze

- store in original container

- for institutional use only

Inactive ingredient

water

GERICARE

NDC 57896-435-16

Celemin-5S (Sorbitol) SOLUTION USP

70% W/W

LAXATIVE

TAMPER EVIDENT: Do not use this product if inner seal over mouth of bottle is missing or broken.

16 FL OZ (473 mL)