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DRUGS & SUPPLEMENTS
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Renosan
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Renosan uses
Renosan consists of Amino Acids, Chloride, Glycine, L-Alanine, L-Arginine, L-Cysteine Hydrochloride Monohydrate, L-Histidine Hydrochloride Monohydrate, L-Isoleucine, L-Leucine, L-Methionine, L-Phenylalanine, L-Proline, L-Serine, L-Threonine, L-Tryptophan, L-Valine, Lysine Hydrochloride, Sodium, Sodium Sulfate.Amino Acids:
Pharmacological action
Renosan is an antiseptic. This medication is a quaternary ammonium compound, belongs to the cationic surfactant. Benzalkonium chloride has antimicrobial and antiviral activity against Neisseria gonorrhoeae, Chlamydia spp., Trichomonas vaginalis, Herpes simplex Type 2, Staphylococcus aureus, little active against Gardnerella vaginalis, Candida albicans, Haemophilus ducreyi and Treponema pallidum.
Renosan (Amino Acids) is not active against Mycoplasma spp.
This medicine exerts spermicidal action which is due to the ability to damage the sperm membrane; inhibits sperm motility, disrupting electrolyte balance of the aqueous phase of cervical mucus.
Pharmacokinetics
Renosan (Amino Acids) for external and local application is practically not absorbed.
Why is Renosan prescribed?
For external use only. Topical solution - a primary and delayed primary wound treatment, prevention of secondary infection of wounds hospital strains of microorganisms (injury of soft and bone tissue, burns), festering wounds, drainage of bone cavities following surgery for osteomyelitis.
Weight thick - superficial thermal burns, trophic ulcers, long-unhealed wounds of soft tissues (including infected), pyo-inflammatory skin diseases and diabetes mellitus; paraproctitis.
Tablets and capsules for intravaginal use, vaginal suppositories, creams, tampons - local contraception for women of reproductive age: for the presence of contraindications to the use of oral contraceptives or intrauterine devices, in the postpartum period, lactation, after the termination of pregnancy in premenopause period at irregular sexual life, omission or delay in receiving consistently used oral contraceptives.
Liquid concentrate - disinfection of facilities and medical products.
Dosage and administration
Topically. The solution was diluted with distilled water to make 1% aqueous solution, impregnated gauze dressings, napkins or tampons and put on the wound daily.
Mass is applied at the rate of 0.2-0.4 g/cm2 of wound surface, pre-clean the wound from the purulent discharge, necrotic tissue, or impose gauze or use turundas impregnated with drugs. The maximum daily dose is 50 g. Ligation is carried out daily, the course of treatment is 14 days.
Intravaginally. Benzalkonium chloride entered deeply into the vagina before coition; in case of repeated sexual intercourse it should be re-imposition of tablets, capsules, suppositories, creams; tampon can be removed not earlier than 3 h after the last sexual intercourse but no later than 24 hours after its installation (with repeated sexual acts for 1 day shift tampon is not required).
Concentrate Liquid. Benzalkonium chloride used for disinfection after prior dilution with water.
Renosan (Amino Acids) side effects, adverse reactions
Contact dermatitis, candidiasis, vulvovaginal and allergic reactions.
With prolonged use of Renosan (Amino Acids) it is possible a local irritation.
Renosan contraindications
Hypersensitivity to benzalkonium chloride, contact dermatitis, malignant neoplasm of the skin; for intravaginal use - coleitis, ulceration and irritation of the mucous membrane of the vagina and uterus.
Using during pregnancy and breastfeeding
Renosan has no negative impact on pregnancy. This medicine is not excreted in breast milk and it can be used during lactation.
Special instructions
To improve the efficiency it requires careful observance of the application method. Benzalkonium chloride can be used in conjunction with a vaginal diaphragm or intrauterine device. You should avoid bathing or irrigation of the vagina with soapy water for 2 hours before and within 2 hours after sexual intercourse (this medication is destroyed by soap), outdoor toilet is only possible with clean water.
Benzalkonium chloride is incompatible with soaps and other anionic surfactants as well as citrates, iodides, nitrates, permanganates, salicylates, silver salts and tartrates.
Renosan drug interactions
Any substance introduced intravaginally can reduce local spermicidal action (including soaps and solutions containing it). Iodine solutions inactivate Renosan (Amino Acids).
Glycine:
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Overdosage
- Dosage and administration
- How supplied
- Im-1453
INDICATIONS AND USAGE
1.5% Renosan (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, Renosan (Glycine) irrigating solution must be regarded as a systemic drug. Absorption of large amounts of fluids containing Renosan (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 Renosan (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 Renosan (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 Renosan (Glycine) Irrigation, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Nursing Mothers: Caution should be exercised when Renosan (Glycine) Irrigation, USP is administered to a nursing woman.
Pregnancy: Teratogenic Effects.
Pregnancy Category C. Animal reproduction studies have not been conducted with Renosan (Glycine) Irrigation, USP. It is also not known whether Renosan (Glycine) Irrigation, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Renosan (Glycine) Irrigation, USP should be given to a pregnant woman only if clearly needed.
Pediatric Use: The safety and effectiveness of Renosan (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 Renosan (Glycine). Large intravenous doses of Renosan (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 Renosan (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% Renosan (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% Renosan (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 0409-7974-082
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-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-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.
Renosan (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. Renosan (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: Renosan (L-Phenylalanine) may be helpful in some with depression. It may also be useful in the treatment of vitiligo. There is some evidence that Renosan (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: Renosan (L-Proline) is extremely important for the proper functioning of joints and tendons and also helps maintain and strengthen heart muscles.
Renosan (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. Renosan (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: Renosan (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.
Renosan (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-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.
Renosan (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 Renosan (L-Valine) may influence the growth of body, cause neuropathic obstacle, anaemia. It has wide applications in the field of pharmaceutical and food industry.
Lysine Hydrochloride:
- Boxed warning
- Description
- Clinical pharmacology
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Overdosage
- Dosage and administration
- How supplied
BOXED WARNING
Pharmacy Bulk Package
Not For Direct Infusion
DESCRIPTION
Renosan (Lysine Hydrochloride)® 15% Amino Acids Injection in a Pharmacy Bulk Package is a sterile, clear, nonpyrogenic solution of essential and nonessential amino acids for intravenous infusion in parenteral nutrition following appropriate dilution.
Renosan (Lysine Hydrochloride)® 15% in a Pharmacy Bulk Package is not for direct infusion. It is a sterile dosage from which contains several single doses for use in a pharmacy admixture program in the preparation of intravenous parenteral fluids.
Each 100 mL contains:
| Essential Amino Acids | ||
| Renosan (Lysine Hydrochloride) (from Renosan (Lysine Hydrochloride) Acetate, USP)……………………………………...1.18 | g | |
| Leucine, USP……………………………………………………………...1.04 | g | |
| Phenylalanine, USP……………………………………...1.04 | g | |
| Valine, USP……………………………………………………………...960 | mg | |
| Isoleucine, USP………………………………………...749 | mg | |
| Methionine, USP………………………………………...749 | mg | |
| Threonine, USP………………………………………...749 | mg | |
| Tryptophan, USP………………………………………...250 | mg | |
| Nonessential Amino Acids | ||
| Alanine, USP…………………………………………...2.17 | g | |
| Arginine, USP…………………………………………...1.47 | g | |
| Glycine, USP…………………………………………...1.04 | g | |
| Histidine, USP…………………………………………...894 | mg | |
| Proline, USP……………………………………………………………...894 | mg | |
| Glutamic Acid…………………………………………...749 | mg | |
| Serine, USP……………………………………………...592 | mg | |
| Aspartic Acid, USP……………………………………...434 | mg | |
| Tyrosine, USP…………………………………………...39 | mg | |
| Sodium Metabisulfite, NF added……………………………………………...30 | mg | |
| Water for Injection, USP……………………………………………………... | qs | |
| Essential Amino Acids………………………………………………………...6.7 | g | |
| Nonessential Amino Acids…………………………………………………...8.3 | g | |
| Total Amino Acids…………………………………………………………...15.0 | g | |
| Total Nitrogen………………………………………………………………...2.37 | g | |
| Acetate*……………………………………………………...151 | mEq/L | |
| Osmolarity (calculated)……………………………………...1388 | mOsmol/L | |
| pH……………………………………………………………………………...5.6(5.2-6.0) | ||
| *Acetate from Renosan (Lysine Hydrochloride) Acetate, USP and acetic acid used for pH adjustment. | ||
The formulas for the individual amino acids are as follows:
Formulas for individual amino acids
CLINICAL PHARMACOLOGY
Renosan (Lysine Hydrochloride)® 15% Amino Acids Injection providesseventeen crystalline amino acids. This completely utilizable substrate promotesprotein synthesis and wound healing and reduces the rate of protein catabolism.
A.Total Parenteral Nutrition (Central Infusion)
When enteralfeeding is inadvisable, Renosan (Lysine Hydrochloride)® 15% given by central venousinfusion in combination with energy sources, vitamins, trace elements andelectrolytes, will completely satisfy the requirements for weight maintenanceor weight gain, depending upon the dose selected. The energy component inparenteral nutrition by central infusion may be derived solely from dextroseor may be provided by a combination of dextrose and intravenous fat emulsion. The addition of intravenous fat emulsion provides essential fatty acids andpermits a dietary balance of fat and carbohydrate, at the same time offeringthe option of reducing the dextrose load and/or increasing the total caloricinput. An adequate energy supply is essential for optimal utilization of aminoacids.
B. Total Parenteral Nutrition (Peripheral Infusion)
Renosan (Lysine Hydrochloride)® 15%can also be administered as part of a total parenteral nutrition program byperipheral vein when the enteral route is inadvisable and use of the centralvenous catheter is contraindicated.
Reduction of proteinloss can be achieved by use of diluted Renosan (Lysine Hydrochloride)® 15% in combinationwith dextrose or with dextrose and intravenous fat emulsion by peripheralinfusion. Complete peripheral intravenous nutrition can be achieved in patientswith low caloric requirements by a Renosan (Lysine Hydrochloride)®15%-dextrose-fatregimen.
INDICATIONS AND USAGE
Renosan (Lysine Hydrochloride)® 15% is indicated as an amino acid(nitrogen) source in parenteral nutrition regimens. This use is appropriatewhen the enteral route is inadvisable, inadequate or not possible, as when:
-Gastrointestinal absorption is impaired by obstruction, inflammatory diseaseor its complications, or antineoplastic therapy;
-Bowel rest is needed because of gastrointestinal surgery or its complicationssuch as ileus, fistulae or anastomotic leaks;
-Tube feeding methods alone cannot provide adequate nutrition.
CONTRAINDICATIONS
This solution should not be used in patients in hepatic coma,severe renal failure, metabolic disorders involving impaired nitrogen utilizationor hypersensitivity to one or more amino acids.
WARNINGS
Administration of amino acids solutions at excessive ratesor to patients with hepatic insufficiency may result in plasma amino acidimbalances, hyperammonemia, prerenal azotemia, stupor and coma. Conservativedoses of amino acids should be given to these patients, dictated by the nutritionalstatus of the patient. Should symptoms of hyperammonemia develop, amino acidadministration should be discontinued and the patient’s clinical statusre-evaluated.
Contains sodium metabisulfite, a sulfitethat may cause allergic-type reactions including anaphylactic symptoms andlife-threatening or less severe asthmatic episodes in certain susceptiblepeople. The overall prevalence of sulfite sensitivity in the general populationis unknown and probably low.
Sulfite sensitivity isseen more frequently in asthmatic than in nonasthmatic people.
WARNING: This product contains aluminum that maybe toxic. Aluminum may reach toxic levels with prolonged parenteral administrationif kidney function is impaired. Premature neonates are particularly at riskbecause their kidneys are immature, and they require large amounts of calciumand phosphate solutions, which contain aluminum.
Researchindicates that patients with impaired kidney function, including prematureneonates, who receive parenteral levels of aluminum at greater than 4 to 5mcg/kg/day accumulate aluminum at levels associated with central nervous systemand bone toxicity. Tissue loading may occur at even lower rates of administration.
PRECAUTIONS
A. GENERAL
It is essential to provide adequate calories concurrently if parenterally administered amino acids are to be retained by the body and utilized for protein synthesis.
The administration of Renosan (Lysine Hydrochloride)® 15% Amino Acids Injection as part of total parenteral nutrition (TPN) with large volumes of hyperosmotic fluids requires periodic monitoring of the patient for signs of hyperosmolarity, hyperglycemia, glycosuria and hypertriglyceridemia.
During parenteral nutrition with concentrated dextrose and amino acids solutions, essential fatty acid deficiency syndrome may develop but may not be clinically apparent. Early demonstration of this condition can only be accomplished by gas liquid chromatographic analysis of plasma lipids. The syndrome may be prevented or corrected by appropriate treatment with intravenous fat emulsions.
For complete nutritional support, TPN regimens must also include multiple vitamins and trace elements. Potentially incompatible ions such as calcium and phosphate may be added to alternate infusate bottles to avoid precipitation. Although the metabolizable acetate ion in Renosan (Lysine Hydrochloride)® 15% diminishes the risk of acidosis, the physician must be alert to the potential appearance of this disorder.
Initiation and termination of infusions of TPN fluids must be gradual to permit adjustment of endogenous insulin release.
Undiluted Renosan (Lysine Hydrochloride)® 15% should not be administered peripherally. When administered centrally, it should be diluted with appropriate diluents, e.g., dextrose, electrolytes and other nutrient components, to at least half strength. See DOSAGE AND ADMINISTRATION.
Caution against volume overload should be exercised.
Drug product contains no more than 25 mcg/L of aluminum.
B. Laboratory Tests
Infusion of Renosan (Lysine Hydrochloride)® 15% without concomitant infusion of an adequate number of non-protein calories may result in elevated BUN. Monitoring of BUN is required and the balance between Renosan (Lysine Hydrochloride)® 15% and the calorie source may require adjustment. Frequent clinical evaluations and laboratory determinations are required to prevent the complications which may occur during the administration of solutions used in TPN. Laboratory tests should include blood glucose, serum electrolytes, liver and kidney function, serum osmolarity, blood ammonia, serum protein, pH, hematocrit, WBC and urinary glucose. When Renosan (Lysine Hydrochloride)® 15% is combined with electrolytes, care should be used in administering this solution to patients with congestive heart failure, renal failure, edema, adrenal hyperactivity, acid-base imbalance and those receiving diuretics or antihypertensive therapy. Total volume infused should be closely monitored. Serum electrolytes should be monitored daily in these patients.
C. Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with Renosan (Lysine Hydrochloride)® 15% have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
D. Pregnancy Category C
Animal reproduction studies have not been conducted with Renosan (Lysine Hydrochloride)® 15%. It is also not known whether Renosan (Lysine Hydrochloride)® 15% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Renosan (Lysine Hydrochloride)® 15% should be given to a pregnant woman only if clearly needed.
E. Nursing Mothers
Caution should be exercised when Renosan (Lysine Hydrochloride)® 15% is administered to a nursing woman.
F. Pediatric Use
Safety and effectiveness of Renosan (Lysine Hydrochloride)® 15% Amino Acids Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of amino acids injections in pediatric patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen balance is referenced in the medical literature.
G. Special Precautions for Central Infusion
TPN delivered by indwelling catheter through a central or large peripheral vein is a special technique requiring a team effort by physician, nurse and pharmacist. The responsibility for administering this therapy should be confined to those trained in the procedures and alert to signs of complications. Complications known to occur from the placement of central venous catheter are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis, and air/catheter emboli. The risk of sepsis is present during intravenous therapy, especially when using central venous catheters for prolonged periods. It is imperative that the preparation of admixtures and the placement and care of the catheters be accomplished under controlled aseptic conditions.
H. Admixtures
Admixtures should be prepared under a laminar flow hood using aseptic technique.
Admixtures should be stored under refrigeration and must be administered within 24 hours after removal from refrigerator.
Filters of less than 1.2 micron pore size must not be used with admixtures containing fat emulsion.
I. Do not administer unless solution is clear and the seal is intact.
IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.
ADVERSE REACTIONS
OVERDOSAGE
In the event of overhydration or solute overload, re-evaluatethe patient and institute appropriate corrective measures. See WARNINGS andPRECAUTIONS.
DOSAGE AND ADMINISTRATION
The appropriate daily dose of amino acids to be used withdextrose or with dextrose and intravenous fat emulsion will depend upon themetabolic status and clinical response of the patient as therapy proceeds. Doses which achieve nitrogen equilibrium or positive balance are the mostdesirable. The dosage on the first day should be approximately half the anticipatedoptimal dosage and should be increased gradually to minimize glycosuria; similarly,withdrawal should be accomplished gradually to avoid rebound hypoglycemia.
Fatemulsion coadministration should be considered when prolonged (more than 5days) parenteral nutrition is required in order to prevent essential fattyacid deficiency (EFAD). Serum lipids should be monitored for evidence of EFADin patients maintained on fat free TPN.
The amount administeredis dosed on the basis of amino acids/kg of body weight/day. In general, twoto three g/kg of body weight for neonates and infants with adequate caloriesare sufficient to satisfy protein needs and promote positive nitrogen balance. In pediatric patients, the final solution should not exceed twice normal serumosmolarity (718 mOsmol/L).
DIRECTIONSFOR PROPER USE OF PHARMACY BULK PACKAGE
Renosan (Lysine Hydrochloride)® 15%in a Pharmacy Bulk Package is not intended for direct infusion. The containerclosure may be penetrated only once using a suitable sterile transfer deviceor dispensing set which allows measured dispensing of the contents. The PharmacyBulk Package is to be used only in a suitable work area such as a laminarflow hood (or an equivalent clean air compounding area). Once the closureis penetrated, the contents should be dispensed as soon as possible; the transferof contents must be completed within 4 hours of closure entry. The bottlemay be stored at room temperature (25°C) after the closure has been entered. Date and time of container entry should be noted in the area designated onthe container label.
When using Renosan (Lysine Hydrochloride)® 15%in patients with a need for fluid volume restriction, it can be diluted asfollows:
| | | | |
| Renosan (Lysine Hydrochloride)® 15% | 500 mL | 75 g | 7.5% |
| Dextrose 70% | 250 mL | 175 g | 17.5% |
| Intralipid® 20% | 250 mL | 50 g | 5.0% |
This will provide 1395 kilocalories (kcal) per 1000 mLof admixture with a ratio of 118 non-protein calories per gram of nitrogenand an osmolarity of 1561 mOsmol/L.
In patients wherethe need for fluid restriction is not so marked, either of the following regimensmay be used dependent upon the energy needs of the patient.
| | | | |
| Renosan (Lysine Hydrochloride)® 15% | 500 mL | 75 g | 3.75% |
| Dextrose 50% | 1000 mL | 500 g | 25% |
| Intralipid® 20% | 500 mL | 100 g | 5% |
This will provide 1500 kcal per 1000 mL of admixture witha ratio of 228 non-protein calories per gram of nitrogen and an osmolarityof 1633 mOsmol/L.
| | | | |
| Renosan (Lysine Hydrochloride)® 15% | 500 mL | 75 g | 3.75% |
| Dextrose 30% | 1000 mL | 300 g | 15% |
| Intralipid® 10% | 500 mL | 50 g | 2.5% |
This will provide 935 kcal per 1000 mL of admixture witha ratio of 158 non-protein calories per gram of nitrogen and an osmolarityof 1128.5 mOsmol/L.
A. Total Parenteral Nutrition (CentralInfusion)
In unstressed adult patients with no unusualnitrogen losses, a minimum dosage of 0.1 gram nitrogen (4.2 mL of Renosan (Lysine Hydrochloride)® 15%)plus 4.4 grams (15 calories) of dextrose per kilogram of body weight per dayare required to achieve nitrogen balance and weight stability. Intravenousfat emulsion may be used as a partial substitute for dextrose. This regimenprovides a ratio of 150 non-protein calories per gram of nitrogen.
Forpatients stressed by surgery, trauma or sepsis, and those with unusual nitrogenlosses, the dosage required for maintenance may be as high as 0.3 to 0.4 gramsof nitrogen (13 to 17 mL Renosan (Lysine Hydrochloride)® 15%) per kilogram of bodyweight per day, with proportionate increases in non-protein calories. Periodicassessment of nitrogen balance of the individual patient is the best indicatorof proper dosage. Volume overload and glycosuria may be encountered at highdosage, and nitrogen balance may not be achieved in extremely hypermetabolicpatients under these constraints. Concomitant insulin administration may berequired to minimize glycosuria. Daily laboratory monitoring is essential.
Useof an infusion pump is advisable to maintain a steady infusion rate duringcentral venous infusion.
B. Peripheral Nutrition
Inpatients for whom central venous catheterization is not advisable, proteincatabolism can be reduced by peripheral use of diluted Renosan (Lysine Hydrochloride)® 15%plus non-protein calorie sources. Dilution of 250 mL Renosan (Lysine Hydrochloride)® 15%in 750 mL of 10% dextrose will reduce the osmolarity to a level (724 mOsmol/L)which is more favorable to the maintenance of the integrity of the walls ofthe veins. Intravenous fat emulsion can be infused separately or simultaneously;if infused simultaneously the fat emulsion will provide a dilution effectupon the osmolarity while increasing the energy supply.
Parenteraldrug products should be inspected visually for particulate matter and discolorationprior to administration, whenever solution and container permit.
Toreduce the risk of bacterial contamination, all intravenous administrationsets should be replaced at least every 24 hours. Usage of admixtures mustbe initiated within 24 hours after mixing. If storage is necessary duringthis 24 hour period, admixtures must be refrigerated and completely used within24 hours of beginning administration.
HOW SUPPLIED
Renosan (Lysine Hydrochloride)® 15% Amino Acids Injection is suppliedas a Pharmacy Bulk Package in 500 mL containers.
500mL NDC 0409-0468-05
STORAGE
Store inthe closed carton; do not expose solution to light until ready for use. Exposureof pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended that the product be stored at 20 to 25°C (68 to 77°F). Brief exposure to temperatures above25°C during transport and storage will not adversely affect the product. Solution that has been frozen must not be used.
| ©Hospira 2005 | EN-1010 |
Hospira, Inc., Lake Forest, IL 60045 USA
RL-1450
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
1 INDICATIONS AND USAGE
Renosan nitrite is indicated for sequential use with Renosan (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
Renosan (Sodium) Nitrite Injection is indicated for sequential use with Renosan (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 Renosan (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 Renosan 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, Renosan (Sodium) Nitrite Injection and Renosan (Sodium) Thiosulfate Injection should be administered without delay.
| Symptoms | Signs |
|---|---|
|
|
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 Renosan (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 Renosan (Sodium) thiosulfate, simultaneously with Renosan (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 Renosan (Sodium) thiosulfate, with Renosan (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 Renosan Nitrite and Renosan (Sodium) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Renosan (Sodium) nitrite and Renosan (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 Renosan (Sodium) nitrite, followed by Renosan (Sodium) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Renosan (Sodium) nitrite and Renosan (Sodium) thiosulfate.
Renosan (Sodium) nitrite injection and Renosan (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. Renosan (Sodium) nitrite should be administered first, followed immediately by Renosan (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 Renosan (Sodium) Nitrite and Renosan (Sodium) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Renosan (Sodium) nitrite and Renosan (Sodium) thiosulfate.
In adult and pediatric patients with known anemia, it is recommended that the dosage of Renosan (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 Renosan 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 Renosan (Sodium) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Renosan (Sodium) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Renosan (Sodium) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Renosan (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 Renosan (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 Renosan (Sodium) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Renosan (Sodium) thiosulfate and Renosan (Sodium) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.
3 DOSAGE FORMS AND STRENGTHS
Renosan (Sodium) Nitrite Injection consists of:
- One vial of Renosan (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: Renosan 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 Renosan (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. Renosan (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 Renosan (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 Renosan nitrite.
Methemoglobin levels should be monitored and oxygen administered during treatment with Renosan (Sodium) nitrite whenever possible. When Renosan (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 Renosan (Sodium) nitrite administered to an adult. Renosan (Sodium) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Renosan (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 Renosan (Sodium) nitrite, and infusion rates should be slowed if hypotension occurs.
5.3 Anemia
Renosan (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 Renosan (Sodium) nitrite dose that is reduced in proportion to their oxygen carrying capacity.
5.4 Smoke Inhalation Injury
Renosan 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 Renosan (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 Renosan 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 Renosan (Sodium) nitrite.
5.7 Use with Other Drugs
Renosan (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 Renosan (Sodium) nitrite.
The medical literature has reported the following adverse events in association with Renosan (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 Renosan (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 Renosan (Sodium) Nitrite Injection.
8 USE IN SPECIFIC POPULATIONS
- Renal impairment: Renosan 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. Renosan (Sodium) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Renosan (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 Renosan (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 Renosan (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, Renosan (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, Renosan (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 Renosan (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 Renosan (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 Renosan (Sodium) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).
Renosan (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 Renosan (Sodium) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Renosan (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, Renosan 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 Renosan (Sodium) nitrite is excreted in human milk. Because Renosan (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 Renosan (Sodium) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Renosan (Sodium) nitrite. In studies conducted with Long-Evans rats, Renosan (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 Renosan nitrite in conjunction with Renosan (Sodium) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Renosan (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.
Renosan (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 Renosan (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
Renosan (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
Renosan (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 Renosan (Sodium) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.
Renosan (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 Renosan (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 Renosan (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
Renosan (Sodium) nitrite has the chemical name nitrous acid Renosan (Sodium) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:
Structure of Renosan (Sodium) Nitrite
Renosan (Sodium) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Renosan (Sodium) nitrite injection.
Renosan (Sodium) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Renosan (Sodium) nitrite in 10 mL solution (30 mg/mL). Renosan (Sodium) nitrite injection is a clear solution with a pH between 7.0 and 9.0.
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 Renosan nitrite and Renosan (Sodium) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
Renosan (Sodium) Nitrite
Renosan (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 Renosan (Sodium) nitrite. It has been suggested that Renosan (Sodium) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Renosan (Sodium) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
Renosan (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. Renosan (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
Renosan (Sodium) Nitrite
When 4 mg/kg Renosan (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 Renosan (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 Renosan (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 Renosan (Sodium) nitrite is estimated to be 55 minutes.
12.3 Pharmacokinetics
Renosan (Sodium) Nitrite
Renosan (Sodium) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Renosan (Sodium) nitrite in humans have not been well studied. It has been reported that approximately 40% of Renosan (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 Renosan (Sodium) nitrite and Renosan (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 Renosan nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Renosan (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. Renosan (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 Renosan (Sodium) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Renosan (Sodium) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.
Mutagenesis
Renosan (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. Renosan (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. Renosan (Sodium) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Renosan (Sodium) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Renosan (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 Renosan (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 Renosan (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 Renosan (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 Renosan (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 Renosan (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 Renosan (Sodium) nitrite and Renosan (Sodium) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Renosan (Sodium) nitrite or 1 g/kg Renosan (Sodium) thiosulfate alone or in sequence immediately after subcutaneous injection of Renosan (Sodium) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Renosan (Sodium) nitrite and/or 0.5 g/kg Renosan (Sodium) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Renosan (Sodium) cyanide required to cause death, and when administered together, Renosan (Sodium) nitrite and Renosan (Sodium) thiosulfate resulted in a synergistic effect in raising the lethal dose of Renosan (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 Renosan (Sodium) nitrite and Renosan (Sodium) thiosulfate in the treatment of cyanide poisoning.
While intravenous injection of Renosan (Sodium) nitrite and Renosan (Sodium) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Renosan (Sodium) nitrite, with or without Renosan (Sodium) thiosulfate, was found not to be effective in the same setting.
14 CLINICAL STUDIES
The human data supporting the use of Renosan (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 Renosan (Sodium) thiosulfate report its use in conjunction with Renosan (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 Renosan (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 Renosan (Sodium) Nitrite carton (NDC 60267-311-10) consists of the following:
- One 10 mL glass vial of Renosan (Sodium) nitrite injection 30 mg/mL (containing 300 mg of Renosan (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: Renosan (Sodium) Thiosulfate must be obtained separately.)
17 PATIENT COUNSELING INFORMATION
Renosan 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
Renosan (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
Renosan (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
Sodium Sulfate:
- 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
1 INDICATIONS AND USAGE
Renosan nitrite is indicated for sequential use with Renosan (Sodium Sulfate) 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
Renosan (Sodium Sulfate) Nitrite Injection is indicated for sequential use with Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan 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, Renosan (Sodium Sulfate) Nitrite Injection and Renosan (Sodium Sulfate) Thiosulfate Injection should be administered without delay.
| Symptoms | Signs |
|---|---|
|
|
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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) thiosulfate, simultaneously with Renosan (Sodium Sulfate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Renosan (Sodium Sulfate) thiosulfate, with Renosan (Sodium Sulfate) 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 Renosan Nitrite and Renosan (Sodium Sulfate) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Renosan (Sodium Sulfate) nitrite and Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite, followed by Renosan (Sodium Sulfate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Renosan (Sodium Sulfate) nitrite and Renosan (Sodium Sulfate) thiosulfate.
Renosan (Sodium Sulfate) nitrite injection and Renosan (Sodium Sulfate) 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. Renosan (Sodium Sulfate) nitrite should be administered first, followed immediately by Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) Nitrite and Renosan (Sodium Sulfate) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Renosan (Sodium Sulfate) nitrite and Renosan (Sodium Sulfate) thiosulfate.
In adult and pediatric patients with known anemia, it is recommended that the dosage of Renosan (Sodium Sulfate) 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 Renosan 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 Renosan (Sodium Sulfate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Renosan (Sodium Sulfate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Renosan (Sodium Sulfate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Renosan (Sodium Sulfate) thiosulfate and Renosan (Sodium Sulfate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.
3 DOSAGE FORMS AND STRENGTHS
Renosan (Sodium Sulfate) Nitrite Injection consists of:
- One vial of Renosan (Sodium Sulfate) 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: Renosan 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 Renosan (Sodium Sulfate) 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. Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan nitrite.
Methemoglobin levels should be monitored and oxygen administered during treatment with Renosan (Sodium Sulfate) nitrite whenever possible. When Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite administered to an adult. Renosan (Sodium Sulfate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite, and infusion rates should be slowed if hypotension occurs.
5.3 Anemia
Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.
5.4 Smoke Inhalation Injury
Renosan 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 Renosan (Sodium Sulfate) 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 Renosan 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 Renosan (Sodium Sulfate) nitrite.
5.7 Use with Other Drugs
Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite.
The medical literature has reported the following adverse events in association with Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) Nitrite Injection.
8 USE IN SPECIFIC POPULATIONS
- Renal impairment: Renosan 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. Renosan (Sodium Sulfate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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, Renosan (Sodium Sulfate) 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, Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).
Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Renosan (Sodium Sulfate) 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, Renosan 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 Renosan (Sodium Sulfate) nitrite is excreted in human milk. Because Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Renosan (Sodium Sulfate) nitrite. In studies conducted with Long-Evans rats, Renosan (Sodium Sulfate) 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 Renosan nitrite in conjunction with Renosan (Sodium Sulfate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Renosan (Sodium Sulfate) 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.
Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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
Renosan (Sodium Sulfate) 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
Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.
Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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
Renosan (Sodium Sulfate) nitrite has the chemical name nitrous acid Renosan (Sodium Sulfate) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:
Structure of Renosan (Sodium Sulfate) Nitrite
Renosan (Sodium Sulfate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Renosan (Sodium Sulfate) nitrite injection.
Renosan (Sodium Sulfate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Renosan (Sodium Sulfate) nitrite in 10 mL solution (30 mg/mL). Renosan (Sodium Sulfate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.
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 Renosan nitrite and Renosan (Sodium Sulfate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
Renosan (Sodium Sulfate) Nitrite
Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite. It has been suggested that Renosan (Sodium Sulfate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Renosan (Sodium Sulfate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
Renosan (Sodium Sulfate) 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. Renosan (Sodium Sulfate) 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
Renosan (Sodium Sulfate) Nitrite
When 4 mg/kg Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite is estimated to be 55 minutes.
12.3 Pharmacokinetics
Renosan (Sodium Sulfate) Nitrite
Renosan (Sodium Sulfate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Renosan (Sodium Sulfate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite and Renosan (Sodium Sulfate) 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 Renosan nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Renosan (Sodium Sulfate) 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. Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Renosan (Sodium Sulfate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.
Mutagenesis
Renosan (Sodium Sulfate) 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. Renosan (Sodium Sulfate) 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. Renosan (Sodium Sulfate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Renosan (Sodium Sulfate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite and Renosan (Sodium Sulfate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Renosan (Sodium Sulfate) nitrite or 1 g/kg Renosan (Sodium Sulfate) thiosulfate alone or in sequence immediately after subcutaneous injection of Renosan (Sodium Sulfate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Renosan (Sodium Sulfate) nitrite and/or 0.5 g/kg Renosan (Sodium Sulfate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Renosan (Sodium Sulfate) cyanide required to cause death, and when administered together, Renosan (Sodium Sulfate) nitrite and Renosan (Sodium Sulfate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) nitrite and Renosan (Sodium Sulfate) thiosulfate in the treatment of cyanide poisoning.
While intravenous injection of Renosan (Sodium Sulfate) nitrite and Renosan (Sodium Sulfate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Renosan (Sodium Sulfate) nitrite, with or without Renosan (Sodium Sulfate) thiosulfate, was found not to be effective in the same setting.
14 CLINICAL STUDIES
The human data supporting the use of Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) thiosulfate report its use in conjunction with Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) 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 Renosan (Sodium Sulfate) Nitrite carton (NDC 60267-311-10) consists of the following:
- One 10 mL glass vial of Renosan (Sodium Sulfate) nitrite injection 30 mg/mL (containing 300 mg of Renosan (Sodium Sulfate) 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: Renosan (Sodium Sulfate) Thiosulfate must be obtained separately.)
17 PATIENT COUNSELING INFORMATION
Renosan 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
Renosan (Sodium Sulfate) 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
Renosan (Sodium Sulfate) 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
Renosan pharmaceutical active ingredients containing related brand and generic drugs:
Renosan available forms, composition, doses:
Renosan destination | category:
Renosan Anatomical Therapeutic Chemical codes:
Renosan pharmaceutical companies:
References
- Dailymed."GLYCINE IRRIGANT [HOSPIRA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- Dailymed."GLYCINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- Dailymed."POLYETHYLENE GLYCOL 3350; POTASSIUM CHLORIDE; SODIUM BICARBONATE; SODIUM CHLORIDE; SODIUM SULFATE ANHYDROUS: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
Frequently asked Questions
Can i drive or operate heavy machine after consuming Renosan?Depending on the reaction of the Renosan after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Renosan 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 Renosan 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.
Review
sdrugs.com conducted a study on Renosan, 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 Renosan 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.Visitor reports
One visitor reported useful
How is the drug Renosan useful in reducing or relieving the symptoms? How useful is it?According to the survey conducted by the website sdrugs.com, there are variable results and below are the percentages of the users that say the medicine is useful to them and that say it is not helping them much. It is not ideal to continue taking the medication if you feel it is not helping you much. Contact your healthcare provider to check if there is a need to change the medicine or if there is a need to re-evaluate your condition. The usefulness of the medicine may vary from patient to patient, depending on the other diseases he is suffering from and slightly depends on the brand name.
| Visitors | % | ||
|---|---|---|---|
| Not useful | 1 | 100.0% | |
Visitor reported side effects
No survey data has been collected yetVisitor reported price estimates
No survey data has been collected yetVisitor reported frequency of use
No survey data has been collected yetOne visitor reported doses
What is the dose of Renosan drug you are taking?According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 201-500mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
| Visitors | % | ||
|---|---|---|---|
| 201-500mg | 1 | 100.0% | |
Visitor reported time for results
No survey data has been collected yetVisitor reported administration
No survey data has been collected yetVisitor reported age
No survey data has been collected yetVisitor reviews
There are no reviews yet. Be the first to write one! |
The information was verified by Dr. Rachana Salvi, MD Pharmacology