Alka-Seltzer XS

Acetaminophen:

• Pharmacological action
• Why is Alka-Seltzer XS (Acetaminophen) prescribed?
• Alka-Seltzer XS dosage and administration
• Alka-Seltzer XS side effects, adverse reactions
• Contraindications
• Using during pregnancy and breastfeeding
• Special Instructions
• Alka-Seltzer XS (Acetaminophen) Drug Interactions
• Alka-Seltzer XS in case of emergency / overdose
• Alka-Seltzer XS (Acetaminophen) reviews

Pharmacological action

Alka-Seltzer XS is an analgesic-antipyretic. It has analgesic, antipyretic and weak anti-inflammatory action. The mechanism of action is associated with inhibition of prostaglandin synthesis, the predominant influence on the thermoregulation center in the hypothalamus, enhances heat transfer.

Why is Alka-Seltzer XS (Acetaminophen) prescribed?

Pain weak and moderate intensity of different genesis (including headache, migraine, toothache, neuralgia, myalgia, algomenorrhea; pain in trauma, burns). Fever in infectious and inflammatory diseases.

Alka-Seltzer XS dosage and administration

Oral or rectally adults and adolescents with a body weight over 60 kg is used in a single dose of 500 mg, the multiplicity of admission - up to 4 times / Maximum duration of treatment - 5-7 days.

Maximum dose: single - 1 g, daily - 4 g.

Single dose for oral administration for children aged 6-12 years - 250-500 mg, 1-5 years - 120-250 mg, from 3 months to 1 year - 60-120 mg, up to 3 months - 10 mg / kg. Single dose rectal in children aged 6-12 years - 250-500 mg, 1-5 years - 125-250 mg.

Multiplicity - 4 at intervals of not less than 4 h. The maximum duration of treatment - 3 days.

Maximum dose: 4 single dose per day.

Alka-Seltzer XS side effects, adverse reactions

Digestive system: rarely - dyspepsia; long-term use at high doses - hepatotoxic effects, methemoglobinemia, renal dysfunction and liver, hypochromic anemia. Hemopoietic system: rarely - thrombocytopenia, leukopenia, pancytopenia, neutropenia, agranulocytosis. Allergic reactions: rarely - skin rash, itching, hives.

Contraindications

Chronic active alcoholism, increased sensitivity to Alka-Seltzer XS, marked disturbances of liver function and / or kidney disease, anemia, pregnancy (I term).

Using during pregnancy and breastfeeding

Alka-Seltzer XS (Acetaminophen) crosses the placental barrier. So far, no observed adverse effects of Alka-Seltzer XS (Acetaminophen) on the fetus in humans.

Alka-Seltzer XS (Acetaminophen) is excreted in breast milk: the content in milk was 0.04-0.23% of the dose adopted mother.

If necessary, use of Alka-Seltzer XS (Acetaminophen) during pregnancy and lactation (breastfeeding) should carefully weigh the potential benefits of therapy for the mother and the potential risk to the fetus or child.

In experimental studies found no embryotoxic, teratogenic and mutagenic action of Alka-Seltzer XS (Acetaminophen).

Special Instructions

Alka-Seltzer XS is used with caution in patients with disorders of the liver and kidneys, with benign hyperbilirubinemia, as well as in elderly patients.

With prolonged use of Alka-Seltzer XS (Acetaminophen) is necessary to monitor patterns of peripheral blood and functional state of the liver.

Used for treatment of premenstrual tension syndrome in combination with pamabrom (diuretic, a derivative of xanthine) and mepyramine (Histamine H1-receptors blocker).

Alka-Seltzer XS (Acetaminophen) Drug Interactions

With the simultaneous use with inducers of microsomal liver enzymes, means having hepatotoxic effect, increasing the risk of hepatotoxic action of Alka-Seltzer XS (Acetaminophen).

With the simultaneous use of anticoagulants may be slight to moderate increase in prothrombin time.

With the simultaneous use of anticholinergics may decrease absorption of Alka-Seltzer XS (Acetaminophen).

With the simultaneous use of oral contraceptives accelerated excretion of Alka-Seltzer XS (Acetaminophen) from the body and may reduce its analgesic action.

With the simultaneous use with urological means reduced their effectiveness.

With the simultaneous use of activated charcoal reduced bioavailability of Alka-Seltzer XS (Acetaminophen).

When Alka-Seltzer XS (Acetaminophen) applied simultaneously with diazepam may decrease excretion of diazepam.

There have been reports about the possibility of enhancing mielodepression effect of zidovudine while applying with Alka-Seltzer XS (Acetaminophen). A case of severe toxic liver injury.

Described cases of toxic effects of Alka-Seltzer XS (Acetaminophen), while the use of isoniazid.

When applied simultaneously with carbamazepine, phenytoin, phenobarbital, primidonom decreases the effectiveness of Alka-Seltzer XS (Acetaminophen), which is caused by an increase in its metabolism and excretion from the body. Cases of hepatotoxicity, while the use of Alka-Seltzer XS (Acetaminophen) and phenobarbital.

In applying cholestyramine a period of less than 1 h after administration of Alka-Seltzer XS (Acetaminophen) may decrease of its absorption.

At simultaneous application with lamotrigine moderately increased excretion of lamotrigine from the body.

With the simultaneous use of metoclopramide may increase absorption of Alka-Seltzer XS (Acetaminophen) and its increased concentration in blood plasma.

When applied simultaneously with probenecid may decrease clearance of Alka-Seltzer XS (Acetaminophen), with rifampicin, sulfinpyrazone - may increase clearance of Alka-Seltzer XS (Acetaminophen) due to increasing its metabolism in the liver.

At simultaneous application of Alka-Seltzer XS (Acetaminophen) with ethinylestradiol increases absorption of Alka-Seltzer XS (Acetaminophen) from the gut.

Enhances the effect of indirect anticoagulants (coumarin derivatives and indandione). Antipyretic and analgesic activity of caffeine increases, reduce - rifampicin, phenobarbital and alcohol (accelerated biotransformation, inducing microsomal liver enzymes).

Alka-Seltzer XS in case of emergency / overdose

At a reception in toxic doses (10-15 g in adults) may develop liver necrosis.

Symptoms of overdose may include: nausea, vomiting, loss of appetite, sweating, extreme tiredness, unusual bleeding or bruising, pain in the upper right part of the stomach, yellowing of the skin or eyes, flu-like symptoms

Aspirin:

• Pharmacological action
• Pharmacokinetics
• Why is Alka-Seltzer XS prescribed?
• Dosage and administration
• Alka-Seltzer XS (Aspirin) side effects, adverse reactions
• Alka-Seltzer XS contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Precautionary measures
• Alka-Seltzer XS (Aspirin) drug interactions
• Alka-Seltzer XS in case of emergency / overdose
• Alka-Seltzer XS (Aspirin) reviews

Pharmacological action

Alka-Seltzer XS is a NSAIDs. It has anti-inflammatory, analgesic and antipyretic effect, and inhibits platelet aggregation. The mechanism of action is associated with inhibition of COX activity - the main enzyme metabolism of arachidonic acid which is a precursor of prostaglandins which play a major role in the pathogenesis of inflammation, pain and fever. Reduction of prostaglandins (mainly E1) in the thermoregulation center leads to a decrease in body temperature due to expansion of blood vessels of the skin and increase perspiration. Analgesic effect of Alka-Seltzer XS (Aspirin) is due to both central and peripheral effects. Reduces aggregation, platelet adhesion and thrombus formation through suppression of synthesis of thromboxane A2 in platelets.

Reduces mortality and risk of myocardial infarction in unstable stenocardia. It is effective in primary prevention of cardio-vascular system and secondary prevention of myocardial infarction. At a daily dose of 6 g or more inhibits the synthesis of prothrombin in the liver and increases the prothrombin time. Alka-Seltzer XS (Aspirin) increases fibrinolytic activity of plasma and reduces the concentration of vitamin K-dependent coagulation factors (II, VII, IX, X). Increases the rate of hemorrhagic complications in carrying out surgical procedures, increases the risk of bleeding during therapy with anticoagulants. It stimulates the excretion of uric acid (violating its reabsorption in the renal tubules) but in high doses. The blockade of COX-1 in the mucosa of the stomach leads to inhibition of gastroprotective prostaglandins, which may lead to ulceration of the mucous membrane and subsequent bleeding.

Pharmacokinetics

When administered orally Alka-Seltzer XS (Aspirin) is rapidly absorbed mainly from the proximal small intestine and to a lesser extent from the stomach. The presence of food in the stomach significantly affects the absorption of Alka-Seltzer XS (Aspirin).

Metabolised in the liver by hydrolysis with the formation of salicylic acid with subsequent conjugation with glycine or two drugs. The concentration of salicylates in blood plasma is variable.

About 80% of salicylic acid binds to plasma proteins. Salicylates easily penetrate into many tissues and body fluids, including the cerebrospinal, peritoneal and synovial fluid. In small quantities salicylates are found in brain tissue, traces - in bile, sweat and feces. Quickly penetrates the placental barrier in small amounts excreted in breast milk.

For newborns salicylates may displace bilirubin from its association with albumin and promote bilirubin encephalopathy.

Penetration into the joint cavity is accelerated in the presence of hyperemia and edema, and slows down in the proliferative phase of inflammation.

If you have acidosis most of salicylate becomes unionized acid, good penetration into the tissue, including in the brain.

Alka-Seltzer XS (Aspirin) withdraws mainly by active secretion in the tubules of the kidneys in unchanged form (60%) and in the form of metabolites. The withdraw of unchanged salicylate is dependent on the pH of urine (for alkalinization of urine increases ionized salicylates, worsening their reabsorption and increases excretion). T1/2 of Alka-Seltzer XS (Aspirin) is approximately 15 minutes. T1/2 of salicylate at a reception in low doses is 2-3 h, with an increase in dose may increase to 15-30 hours. Newborns' elimination of salicylate is much slower than in adults.

Why is Alka-Seltzer XS prescribed?

Rheumatism, rheumatoid arthritis, infectious-allergic myocarditis, fever during infectious and inflammatory diseases, pain syndrome, weak and medium intensity of various origins (including neuralgia, myalgia, headache); based prevention of thrombosis and embolism, primary and secondary prevention of myocardial infarction, prevention of violations of cerebral circulation by ischemic type.

In the clinical immunology and allergy: a gradually increasing doses for a prolonged "aspirin" desensitization and the formation of stable tolerance to NSAIDs in patients with "aspirin asthma" and "aspirin triad."

Dosage and administration

Individual. For oral administration dosing of Alka-Seltzer XS regimen depends on indication for use. Usual adult dose when used as antipyretic and analgesic is 500-1000 mg / day (up to 3 g) were divided into 3 admission.

In myocardial infarction, as well as for secondary prevention in patients after myocardial infarction - 40-325 mg 1 time a day (usually 160 mg). As an inhibitor of platelet aggregation - a dose of 300-325 mg / day, for a long time. At the dynamic circulatory disorders in men, cerebral thromboembolism, including to prevent a recurrence - 325 mg / day with gradual increase to a maximum of 1 g / day. For prevention of thrombosis or occlusion of the aortic shunt - by 325 mg every 7 h after intranasal gastric tube set, and then - through the mouth to 325 mg 3 times a day (usually in combination with dipyridamole, which abolished after 1 week, continuing the long-term treatment with Alka-Seltzer XS (Aspirin)).

Alka-Seltzer XS (Aspirin) side effects, adverse reactions

Digestive system: nausea, vomiting, anorexia, epigastric pain, diarrhea; rarely - occurrence of erosive and ulcerative lesions, bleeding from the gastrointestinal tract, abnormal liver function.

Central nervous system: long-term use may be dizziness, headache, reversible visual disturbances, tinnitus, aseptic meningitis.

Hemopoietic system: rarely - thrombocytopenia, anemia.

Blood coagulation system: rarely - haemorrhagic syndrome, prolongation of bleeding time.

Urinary system: rarely - renal dysfunction, with prolonged use - acute kidney failure, nephrotic syndrome.

Allergic reactions: rarely - skin rash, Quincke's edema, bronchospasm, "aspirin triad" (a combination of bronchial asthma, recurrent nasal polyposis, and paranasal sinuses and intolerance of Alka-Seltzer XS (Aspirin) and medicines pirazolonic series).

Other: in some cases - Reye syndrome, long-term use - increased symptoms of chronic heart failure.

Alka-Seltzer XS contraindications

Exacerbation phase of erosive-ulcerative lesions in the gastrointestinal tract, gastro-intestinal bleeding, "aspirin triad", a history of indications urticaria, rhinitis, caused by taking Alka-Seltzer XS (Aspirin) and other NSAIDs, hemophilia, hemorrhagic diathesis, gipoprotrombinemii, dissecting aneurysm of the aorta, portal hypertension, deficiency of vitamin K, liver and / or renal failure, deficiency of glucose-6-phosphate dehydrogenase, Reye syndrome, children's age (under 15 years - the risk of developing Reye syndrome in children with hyperthermia on a background of viral diseases), I and III trimester of pregnancy, lactation, hypersensitivity to Alka-Seltzer XS (Aspirin) and other salicylates.

Using during pregnancy and breastfeeding

Alka-Seltzer XS (acetylsalicylic acid) is contraindicated in I and III trimester of pregnancy. In pregnancy trimester II can a one-off reception on the strict condition.

This medication has a teratogenic effect: when used in the I trimester leads to top palatoschisis, in the III trimester - cause inhibition of labor (inhibition of prostaglandin synthesis), premature closure of the ductus arteriosus in the fetus, pulmonary vascular hyperplasia and hypertension in the pulmonary circulation.

Alka-Seltzer XS (Aspirin) (acetylsalicylic acid) is excreted in breast milk, which increases the risk of bleeding in a child due to dysfunction of platelets, and therefore should not be applied Alka-Seltzer XS (Aspirin) in the mother during lactation.

Special instructions

Alka-Seltzer XS (Aspirin) with caution used in patients with liver diseases and kidney, bronchial asthma, erosive and ulcerative lesions, and bleeding from the digestive tract in history, with increased bleeding or while holding anticoagulant therapy, decompensated congestive heart failure.

Alka-Seltzer XS (Aspirin) even in small doses reduces the excretion of uric acid from the organism that can cause an acute attack of gout in predisposed patients. When conducting long-term therapy and / or use of Alka-Seltzer XS (Aspirin) in high doses required medical supervision and regular monitoring of hemoglobin levels.

The use of Alka-Seltzer XS (Aspirin) as anti-inflammatory drugs in a daily dose of 5-8 g is limited due to the high probability of adverse effects from the gastrointestinal tract.

Before surgery to reduce bleeding during surgery and postoperative period should stop taking salicylates for 5-7 days.

During prolonged therapy is necessary to conduct a general analysis of blood and study of occult blood.

The use of Alka-Seltzer XS (Aspirin) is contraindicated in pediatrics, as in the case of viral infection in children under the influence of Alka-Seltzer XS (Aspirin) increases the risk of developing Reye syndrome. Symptoms of Reye syndrome are prolonged vomiting, acute encephalopathy, liver enlargement.

Duration of treatment (without consulting a doctor) with Alka-Seltzer XS (Aspirin) should not exceed 7 days when administered as analgesic and more than 3 days as an antipyretic.

During treatment the patient should abstain from alcohol.

Precautionary measures

Undesirable combined use with other NSAIDs and glucocorticoids. For 5-7 days before surgery should stop taking.

The probability of NSAID-gastropathy decreases in the appointment after a meal, use of tablets with buffer additives or coated with a special enteric-soluble shell. The risk of hemorrhagic complications is minimal when used in doses less than 100 mg / day.

Note that in predisposed patients Alka-Seltzer XS (Aspirin) (even in small doses) reduces the excretion of uric acid from the body and can cause the development of acute attack of gout.

During prolonged therapy should regularly carry out the analysis of blood and to investigate faeces for occult blood. In connection with the observed cases hepatogenic encephalopathy is not recommended for relief of fever syndrome in children.

Alka-Seltzer XS (Aspirin) drug interactions

With simultaneous use of antacids containing magnesium and / or aluminum hydroxide, slow down and reduce the absorption of Alka-Seltzer XS (Aspirin).

With simultaneous use of calcium channel blockers, means limiting intake of calcium or increasing the excretion of calcium from the body, increases the risk of bleeding.

With simultaneous use with Alka-Seltzer XS (Aspirin) enhances the action of heparin and indirect anticoagulants, hypoglycemic funds derived sulfonylureas, insulin, methotrexate, phenytoin, valproic acid.

With simultaneous use of Alka-Seltzer XS (Aspirin) with SCS increases the risk of ulcerogenic effect and occurrence of gastrointestinal bleeding.

With simultaneous use of decreasing the effectiveness of diuretics (spironolactone, furosemide).

With simultaneous use of other NSAIDs increases the risk of side effects. Alka-Seltzer XS (Aspirin) may reduce plasma concentrations indomethacin, piroxicam.

With simultaneous use of gold drugs Alka-Seltzer XS (Aspirin) can induce liver damage.

With simultaneous use decreases effectiveness of uricosuric medications (including probenecid, sulfinpirazon, benzbromarone).

With simultaneous use of Alka-Seltzer XS (Aspirin) and alendronate sodium may develop severe esophagitis.

With simultaneous use of griseofulvin may be in breach Absorption of Alka-Seltzer XS (Aspirin).

There is one case of spontaneous hemorrhage in the iris while taking Ginkgo Biloba extract on the background of prolonged use of Alka-Seltzer XS (Aspirin) in a dose of 325 mg / day. It is believed that this may be due to additive inhibitory effect on platelet aggregation.

With simultaneous use of dipyridamole may increase C_max of salicylate in plasma and AUC.

When applied simultaneously with Alka-Seltzer XS (Aspirin) increased concentration of digoxin, barbiturates and lithium salts in the blood plasma.

With simultaneous use of salicylates in high doses with carbonic anhydrase inhibitors can intoxication salicylates.

Alka-Seltzer XS (Aspirin) in doses of less than 300 mg have little effect on the effectiveness of captopril and enalapril. When Alka-Seltzer XS (Aspirin) (acetylsalicylic acid) is admistered in high doses may decrease the effectiveness of captopril and enalapril.

With simultaneous application of caffeine increases the rate of absorption, plasma concentrations and bioavailability of Alka-Seltzer XS (Aspirin).

With simultaneous use of Alka-Seltzer XS (Aspirin) with metoprolol may increase C_max of salicylate in blood plasma.

In the application of pentazocine on the background of long-term use of Alka-Seltzer XS (Aspirin) in high doses there is a risk of severe adverse reactions in the kidneys.

With simultaneous application phenylbutazone reduces uricosuria caused by Alka-Seltzer XS (Aspirin).

With simultaneous application of ethanol may exacerbate the effects of Alka-Seltzer XS (Aspirin) on the gastrointestinal tract.

Alka-Seltzer XS in case of emergency / overdose

May occur after receiving a single large dose or prolonged use. If a single dose of less than 150 mg / kg, acute poisoning feel light, 150-300 mg / kg - moderate, when using higher doses - heavy.

Symptoms: salicylism syndrome (nausea, vomiting, tinnitus, blurred vision, dizziness, severe headache, malaise, fever - a poor prognostic sign in adults). More severe poisoning - stupor, convulsions and coma, noncardiogenic pulmonary edema, abrupt dehydration, violations ABE (initially - respiratory alkalosis, then - metabolic acidosis), renal failure and shock.

In chronic overdose concentration determined in plasma are poorly correlated with the severity of intoxication. The greatest risk of chronic intoxication is found among elderly people at reception for a few days more than 100 mg / kg / day. In children and elderly patients the initial signs of salicylism are not always visible, and therefore desirable to periodically determine the concentration of salicylates in the blood. Level above 70 mg% indicates moderate or severe poisoning; above 100 mg% - on extremely heavy, a poor prognosis. If poisoning moderate require hospitalization for at least 24 hours.

Treatment: the provocation of vomiting, the appointment of activated charcoal and laxatives, monitoring ABE and electrolyte balance, depending on the state of metabolism - the introduction of sodium bicarbonate, solution of sodium citrate or sodium lactate. Raising reserve alkalinity increases the excretion of Alka-Seltzer XS (Aspirin) by alkalinization of urine. Alkalinization of urine is shown at the level of salicylates above 40 mg%, is provided in / by infusion of sodium bicarbonate - 88 mEq in 1 liter of 5% glucose solution, the rate of 10-15 ml / kg / h. Restoring BCC and induction of diuresis (achieved by introducing a bicarbonate in the same dose and dilution, repeat 2-3 times); should be aware that intense infusion fluid elderly patients may lead to pulmonary edema. Not recommended the use of acetazolamide for alkalinization of urine (may cause acidemia and enhance the toxic effect of salicylates). Hemodialysis is shown at the level of salicylates over 100-130 mg%, and in patients with chronic poisoning - 40 mg% or lower in the presence of witnesses (refractory acidosis, progressive deterioration, severe damage of the CNS, pulmonary edema and renal failure). When pulmonary edema - a mixture of artificial ventilation, oxygen enriched, in the mode of positive end-expiratory pressure, to treat cerebral edema apply hyperventilation and osmotic diuresis.

Caffeine:

• Alka-Seltzer XS (Caffeine) reviews

Active ingredient (in each tablet)

Alka-Seltzer XS (Caffeine) 200mg

Purpose

Alertness aid

Use

• helps restore mental alertness or wakefulness when experiencing fatigue or drowsiness

Warnings

For occasional use only

Do not use

• in children under 12 years of age
• as a substitute for sleep

When using this product limit the use of Alka-Seltzer XS (Caffeine) containing medications, foods, or beverages because too much Alka-Seltzer XS (Caffeine) may cause nervousness, irritability, sleeplessness, and occasionally, rapid heartbeat. The recommended dose of this product contains about as much Alka-Seltzer XS (Caffeine) as a cup of coffee.

Stop use and ask a doctor if fatigue or drowsiness persists or continues to recur

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

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

Directions

• adults and children 12 years of age and over: take 1 tablet not more often than every 3 to 4 hours.

Other information

• store at room temperature
• avoid excessive heat (greater than 100°F) or humidity

Inactive ingredients

carnauba wax, colloidal silicon dioxide, D&C yellow #10 aluminum lake, dextrose, FD&C yellow #6 aluminum lake, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, starch, titanium dioxide

Questions or comments?

Call toll-free 1-855-874-0970 weekdays

Display Panel Alka-Seltzer XS (Caffeine): 16 ct. Package

Alka-Seltzer XS (Caffeine)^®

CAFFEINE ALERTNESS AID

16 TABLETS

200mg each

FUNCTIONAL Alka-Seltzer XS (Caffeine)^® for Mental Alertness

SAFE & EFFECTIVE

One tablet is equal to about a cup of coffee

Alka-Seltzer XS (Caffeine)^®

Making the Most of Every Day.^®

Tamper Evident Feature: individually sealed in foil for your protection. Do not

use if foil or plastic bubble is torn or punctured.

Vivarin®, Vivarin® and design, stylization and trade dress, and FUNCTIONAL

CAFFEINE® are registered trademarks of Meda AB.

Distributed by:

Meda Consumer Healthcare Inc.

Marietta, GA 30062 ©2011 Meda AB

www.vivarin.com

16 ct. Package

Display Panel Alka-Seltzer XS (Caffeine): 40 ct. Package

SAFE & EFFECTIVE

FUNCTIONAL Alka-Seltzer XS (Caffeine)^® for Mental Alertness

Alka-Seltzer XS (Caffeine)^®

Alka-Seltzer XS (Caffeine) ALERTNESS AID

40 Tablets

200mg each

FUNCTIONAL Alka-Seltzer XS (Caffeine)^® for Mental Alertness

Tamper Evident Feature: Individually sealed in foil for your protection. Do not use if foil or plastic bubble is torn or punctured.

VIVARIN® helps restore mental alertness or wakefulness when experiencing fatigue or drowsiness (FDA approved uses), so you can accomplish all the things you want to do and all the things you need to do.

Vivarin®, Vivarin® and design, stylization and trade dress, and FUNCTIONAL

CAFFEINE® are registered trademarks of Meda AB.

Made in the U.S.A.

Alka-Seltzer XS (Caffeine)^®

Making the Most of Every Day.^®

Distributed by:

Meda Consumer Healthcare Inc.

Marietta, GA 30062 ©2013 Meda AB

www.vivarin.com

40 ct. Package

Citric Acid:

• Description
• Action
• Indications
• Contraindications
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Alka-Seltzer XS (Citric Acid) reviews

Rx Only

DESCRIPTION

The product is a clear, colorless solution containing Alka-Seltzer XS (Citric Acid) Acid USP 640 mg/5 mL, and Hydrous Sodium Citrate USP 490 mg/5 mL. It also contains Methylparaben NF and Propylparaben NF as preservatives. These concentrations yield 1 mEq of sodium, equivalent to 1 mEq of bicarbonate per mL of solution.

ACTION

Oral citrate solution is used as a systemic and urinary alkalinizer. Less than 5% of the citrate is excreted in the urine unchanged, since citrate oxidation is to a great extent complete.

INDICATIONS

Alka-Seltzer XS (Citric Acid)^® is indicated for the treatment of metabolic acidosis. This solution is also useful in conditions where long term maintenance of alkaline urine is needed (e.g. uric acid and cystine calculi of the urinary tract). Alka-Seltzer XS (Citric Acid)^® is also effective in treatment for acidosis of certain renal tubular disorders.

CONTRAINDICATIONS

Alka-Seltzer XS (Citric Acid)^® is contraindicated in patients with severe renal impairment, oliguria or azotemia, untreated Addison's disease, adynamia episodica hereditaria, acute dehydration, heat cramp, anuria, severe myocardial damage, and hyperkalemia.

PRECAUTIONS

The citrate solution should be used with caution in patients with impaired renal function to avoid hypernatremia or alkalosis in the presence of hypocalcemia. Periodic determinations of serum electrolyte levels (especially bicarbonate levels) should be done in patients with renal disease to avoid cardiac failure, hypertension, peripheral and pulmonary edema, and toxemia of pregnancy. The solution should be diluted with water and preferably taken after meals to avoid saline laxative effects.

ADVERSE REACTIONS

Citrate solution is generally well tolerated when given in recommended doses when the patient has normal renal functions.

DOSAGE AND ADMINISTRATION

The dose of Alka-Seltzer XS (Citric Acid)^® is 10 to 30 mL, diluted with water, after meals and at bedtime. The dose should be titrated to achieve desired effects.

HOW SUPPLIED

Alka-Seltzer XS ^® is supplied in 500 mL bottles (NDC 46287-014-01), 30 mL unit dose bottles, 10 bottles per carton (NDC 46287-014-30), and 15 mL unit dose bottles, 10 bottles per carton (NDC 46287-014-15).

PHARMACIST

Dispense in well-closed containers.

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F)..

CMP Pharma, Inc.

Post Office Box 147

Farmville, North Carolina 27828

Revised July 2015

Copyright ^© CMP Pharma, Inc. 2015

NDC 46287-014-01

500 mL

Alka-Seltzer XS (Citric Acid)^®

ORAL CITRATE (SHOHL'S) SOLUTION

CONTAINS: Hydrous Sodium Citrate USP 490 mg/5 mL;

Alka-Seltzer XS (Citric Acid) Acid USP 640 mg/5 mL; Methylparaben NF;

Propylparaben NF; Alcohol USP 0.25%.

USUAL

Dosage: See package insert.

Dispense in a well-closed container.

Store at 20°-25°C (68°-77°F); excursions permitted

to 15°-30°C (59°-86°F). [See USP Controlled Room

Temperature].

Rx Only

LOT:

EXP:

CMP

PHARMA

Farmville, NC 27828

Sodium Bicarbonate:

• 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
• Alka-Seltzer XS (Sodium Bicarbonate) reviews

1 INDICATIONS AND USAGE

Alka-Seltzer XS nitrite is indicated for sequential use with Alka-Seltzer XS (Sodium Bicarbonate) 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

Alka-Seltzer XS (Sodium Bicarbonate) Nitrite Injection is indicated for sequential use with Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS 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, Alka-Seltzer XS (Sodium Bicarbonate) Nitrite Injection and Alka-Seltzer XS (Sodium Bicarbonate) Thiosulfate Injection should be administered without delay.

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

2 DOSAGE AND ADMINISTRATION

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

Alka-Seltzer XS (Sodium Bicarbonate) nitrite injection and Alka-Seltzer XS (Sodium Bicarbonate) 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. Alka-Seltzer XS (Sodium Bicarbonate) nitrite should be administered first, followed immediately by Alka-Seltzer XS (Sodium Bicarbonate) 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.

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

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

3 DOSAGE FORMS AND STRENGTHS

Alka-Seltzer XS (Sodium Bicarbonate) Nitrite Injection consists of:

• One vial of Alka-Seltzer XS (Sodium Bicarbonate) 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: Alka-Seltzer XS 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 Alka-Seltzer XS (Sodium Bicarbonate) 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. Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS nitrite.

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

5.3 Anemia

Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Alka-Seltzer XS 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 Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS 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 Alka-Seltzer XS (Sodium Bicarbonate) nitrite.

5.7 Use with Other Drugs

Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) nitrite.

The medical literature has reported the following adverse events in association with Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Alka-Seltzer XS 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. Alka-Seltzer XS (Sodium Bicarbonate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) 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, Alka-Seltzer XS (Sodium Bicarbonate) 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, Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

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

Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) 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

Alka-Seltzer XS (Sodium Bicarbonate) 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

Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) 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

Alka-Seltzer XS (Sodium Bicarbonate) nitrite has the chemical name nitrous acid Alka-Seltzer XS (Sodium Bicarbonate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Alka-Seltzer XS (Sodium Bicarbonate) Nitrite

Alka-Seltzer XS (Sodium Bicarbonate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Alka-Seltzer XS (Sodium Bicarbonate) nitrite injection.

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

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

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

Alka-Seltzer XS (Sodium Bicarbonate) Nitrite

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

Alka-Seltzer XS (Sodium Bicarbonate) 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. Alka-Seltzer XS (Sodium Bicarbonate) 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

Alka-Seltzer XS (Sodium Bicarbonate) Nitrite

When 4 mg/kg Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Alka-Seltzer XS (Sodium Bicarbonate) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

The human data supporting the use of Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) thiosulfate report its use in conjunction with Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) 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 Alka-Seltzer XS (Sodium Bicarbonate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Alka-Seltzer XS (Sodium Bicarbonate) nitrite injection 30 mg/mL (containing 300 mg of Alka-Seltzer XS (Sodium Bicarbonate) 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: Alka-Seltzer XS (Sodium Bicarbonate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Alka-Seltzer XS 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

Alka-Seltzer XS (Sodium Bicarbonate) 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

Alka-Seltzer XS (Sodium Bicarbonate) 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