Sublimaze

fentanyl citrate

Dosage Form: injection

CII

Rx only

Sublimaze Description

Sublimaze (fentanyl citrate) Injection is a potent narcotic analgesic. Each milliliter of solution contains fentanyl citrate equivalent to 50 mcg of fentanyl base, adjusted to pH 4.0 to 7.5 with sodium hydroxide. Sublimaze is chemically identified as N-(1-phenethyl-4-piperidyl) propionanilide citrate (1:1) with a molecular weight of 528.60. The empirical formula is C22H28N2O • C6H8O7. The structural formula of Sublimaze is:

Sublimaze is a sterile, non-pyrogenic, preservative free aqueous solution for intravenous or intramuscular injection.

Sublimaze - Clinical Pharmacology

Sublimaze (fentanyl citrate) is a narcotic analgesic. A dose of 100 mcg (0.1 mg) (2.0 ml) is approximately equivalent in analgesic activity to 10 mg of morphine or 75 mg of meperidine. The principal actions of therapeutic value are analgesia and sedation. Alterations in respiratory rate and alveolar ventilation, associated with narcotic analgesics, may last longer than the analgesic effect. As the dose of narcotic is increased, the decrease in pulmonary exchange becomes greater. Large doses may produce apnea. Sublimaze appears to have less emetic activity than either morphine or meperidine. Histamine assays and skin wheal testing in man indicate that clinically significant histamine release rarely occurs with Sublimaze. Recent assays in man show no clinically significant histamine release in dosages up to 50 mcg/kg (0.05 mg/kg) (1 ml/kg). Sublimaze preserves cardiac stability, and blunts stress-related hormonal changes at higher doses.

The pharmacokinetics of Sublimaze can be described as a three-compartment model, with a distribution time of 1.7 minutes, redistribution of 13 minutes and a terminal elimination half-life of 219 minutes. The volume of distribution for Sublimaze is 4 L/kg.

Sublimaze plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. It accumulates in skeletal muscle and fat, and is released slowly into the blood. Sublimaze, which is primarily transformed in the liver, demonstrates a high first pass clearance and releases approximately 75% of an intravenous dose in urine, mostly as metabolites with less than 10% representing the unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites.

The onset of action of Sublimaze is almost immediate when the drug is given intravenously; however, the maximal analgesic and respiratory depressant effect may not be noted for several minutes. The usual duration of action of the analgesic effect is 30 to 60 minutes after a single intravenous dose of up to 100 mcg (0.1 mg) (2.0 ml). Following intramuscular administration, the onset of action is from seven to eight minutes, and the duration of action is one to two hours. As with longer acting narcotic analgesics, the duration of the respiratory depressant effect of Sublimaze may be longer than the analgesic effect. The following observations have been reported concerning altered respiratory response to CO2 stimulation following administration of Sublimaze to man.

1. DIMINISHED SENSITIVITY TO CO2 STIMULATION MAY PERSIST LONGER THAN DEPRESSION OF RESPIRATORY RATE. (Altered sensitivity to CO2 stimulation has been demonstrated for up to four hours following a single dose of 600 mcg (0.6 mg) (12 ml) Sublimaze to healthy volunteers.) Sublimaze frequently slows the respiratory rate, duration and degree of respiratory depression being dose related.


2. The peak respiratory depressant effect of a single intravenous dose of Sublimaze is noted 5 to 15 minutes following injection. See also WARNINGS and PRECAUTIONS concerning respiratory depression.

Indications and Usage for Sublimaze

Sublimaze (fentanyl citrate) is indicated:

—

for analgesic action of short duration during the anesthetic periods, premedication, induction and maintenance, and in the immediate postoperative period (recovery room) as the need arises.

—

for use as a narcotic analgesic supplement in general or regional anesthesia.

—

for administration with a neuroleptic as an anesthetic premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia.

—

for use as an anesthetic agent with oxygen in selected high risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopedic procedures.

Contraindications

Sublimaze (fentanyl citrate) is contraindicated in patients with known intolerance to the drug or other opioid agonists.

Warnings

Sublimaze (fentanyl citrate) SHOULD BE ADMINISTERED ONLY BY PERSONS SPECIFICALLY TRAINED IN THE USE OF INTRAVENOUS ANESTHETICS AND MANAGEMENT OF THE RESPIRATORY EFFECTS OF POTENT OPIOIDS.

AN OPIOID ANTAGONIST, RESUSCITATIVE AND INTUBATION EQUIPMENT AND OXYGEN SHOULD BE READILY AVAILABLE.

See also discussion of narcotic antagonists in PRECAUTIONS and OVERDOSAGE.

If Sublimaze is administered with a tranquilizer, the user should become familiar with the special properties of each drug, particularly the widely differing duration of action. In addition, when such a combination is used, fluids and other countermeasures to manage hypotension should be available.

As with other potent narcotics, the respiratory depressant effect of Sublimaze may persist longer than the measured analgesic effect. The total dose of all narcotic analgesics administered should be considered by the practitioner before ordering narcotic analgesics during recovery from anesthesia. It is recommended that narcotics, when required, should be used in reduced doses initially, as low as ¼ to ⅓ those usually recommended.

Sublimaze may cause muscle rigidity, particularly involving the muscles of respiration. This rigidity has been reported to occur or recur infrequently in the extended postoperative period usually following high dose administration. In addition, skeletal muscle movements of various groups in the extremities, neck and external eye have been reported during induction of anesthesia with fentanyl; these reported movements have, on rare occasions, been strong enough to pose patient management problems. This effect is related to the dose and speed of injection and its incidence can be reduced by: 1) administration of up to ¼ of the full paralyzing dose of a non-depolarizing neuromuscular blocking agent just prior to administration of Sublimaze; 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of eyelash reflex when Sublimaze is used in anesthetic doses titrated by slow intravenous infusion; or, 3) simultaneous administration of Sublimaze and a full paralyzing dose of a neuromuscular blocking agent when Sublimaze is used in rapidly administered anesthetic dosages. The neuromuscular blocking agent used should be compatible with the patient's cardiovascular status.

Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of Sublimaze. Where moderate or high doses are used (above 10 mcg/kg), there must be adequate facilities for postoperative observation, and ventilation if necessary, of patients who have received Sublimaze. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression.

Sublimaze may also produce other signs and symptoms characteristic of narcotic analgesics including euphoria, miosis, bradycardia and bronchoconstriction.

Severe and unpredictable potentiation by MAO inhibitors has been reported for other narcotic analgesics. Although this has not been reported for fentanyl, there are insufficient data to establish that this does not occur with fentanyl. Therefore, when fentanyl is administered to patients who have received MAO inhibitors within 14 days, appropriate monitoring and ready availability of vasodilators and beta-blockers for the treatment of hypertension is indicated.

Head Injuries and Increased Intracranial Pressure

Sublimaze should be used with caution in patients who may be particularly susceptible to respiratory depression, such as comatose patients who may have a head injury or brain tumor. In addition, Sublimaze may obscure the clinical course of patients with head injury.

Precautions

General

The initial dose of Sublimaze (fentanyl citrate) should be appropriately reduced in elderly and debilitated patients. The effect of the initial dose should be considered in determining incremental doses.

Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Sublimaze.

Certain forms of conduction anesthesia, such as spinal anesthesia and some peridural anesthetics, can alter respiration by blocking intercostal nerves. Through other mechanisms (see CLINICAL PHARMACOLOGY) Sublimaze can also alter respiration. Therefore, when Sublimaze is used to supplement these forms of anesthesia, the anesthetist should be familiar with the physiological alterations involved, and be prepared to manage them in the patients selected for these forms of anesthesia.

When a tranquilizer is used with Sublimaze, pulmonary arterial pressure may be decreased. This fact should be considered by those who conduct diagnostic and surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient. When high dose or anesthetic dosages of Sublimaze are employed, even relatively small dosages of diazepam may cause cardiovascular depression.

When Sublimaze is used with a tranquilizer, hypotension can occur. If it occurs, the possibility of hypovolemia should also be considered and managed with appropriate parenteral fluid therapy. Repositioning the patient to improve venous return to the heart should be considered when operative conditions permit. Care should be exercised in moving and repositioning of patients because of the possibility of orthostatic hypotension. If volume expansion with fluids plus other countermeasures do not correct hypotension, the administration of pressor agents other than epinephrine should be considered. Epinephrine may paradoxically decrease blood pressure in patients treated with a neuroleptic that blocks alpha adrenergic activity.

Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of Sublimaze combined with a neuroleptic. This might be due to unexplained alterations in sympathetic activity following large doses; however, it is also frequently attributed to anesthetic and surgical stimulation during light anesthesia.

When Sublimaze is used with a neuroleptic and the EEG is used for postoperative monitoring, it may be found that the EEG pattern returns to normal slowly.

Many neuroleptic agents have been associated with QT prolongation, torsades de pointes, and cardiac arrest. Neuroleptic agents should be administered with extreme caution in the presence of risk factors for development of prolonged QT syndrome and torsades de pointes, such as: 1) clinically significant bradycardia (less than 50 bpm), 2) any clinically significant cardiac disease, including baseline prolonged QT interval, 3) treatment with Class I and Class III antiarrhythmics, 4) treatment with monoamine oxidase inhibitors (MAOI's), 5) concomitant treatment with other drug products known to prolong the QT interval and 6) electrolyte imbalance, in particular hypokalemia and hypomagnesemia, or concomitant treatment with drugs (e.g. diuretics) that may cause electrolyte imbalance.

ECG monitoring is indicated when a neuroleptic agent is used in conjunction with Sublimaze as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia.

Vital signs should be monitored routinely.

Respiratory depression caused by opioid analgesics can be reversed by opioid antagonists such as naloxone. Because the duration of respiratory depression produced by Sublimaze may last longer than the duration of the opioid antagonist action, appropriate surveillance should be maintained. As with all potent opioids, profound analgesia is accompanied by respiratory depression and diminished sensitivity to CO2 stimulation which may persist into or recur in the postoperative period. Respiratory depression secondary to chest wall rigidity has been reported in the postoperative period. Intraoperative hyperventilation may further alter postoperative response to CO2. Appropriate postoperative monitoring should be employed to ensure that adequate spontaneous breathing is established and maintained in the absence of stimulation prior to discharging the patient from the recovery area.

Impaired Respiration

Sublimaze should be used with caution in patients with chronic obstructive pulmonary disease, patients with decreased respiratory reserve, and others with potentially compromised respiration. In such patients, narcotics may additionally decrease respiratory drive and increase airway resistance. During anesthesia, this can be managed by assisted or controlled respiration.

Impaired Hepatic or Renal Function

Sublimaze should be administered with caution to patients with liver and kidney dysfunction because of the importance of these organs in the metabolism and excretion of drugs.

Cardiovascular Effects

Sublimaze may produce bradycardia, which may be treated with atropine. Sublimaze should be used with caution in patients with cardiac bradyarrhythmias.

Drug Interactions

Other CNS depressant drugs (e.g. barbiturates, tranquilizers, narcotics and general anesthetics) will have additive or potentiating effects with Sublimaze. When patients have received such drugs, the dose of Sublimaze required will be less than usual. Following the administration of Sublimaze, the dose of other CNS depressant drugs should be reduced.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or mutagenicity studies have been conducted with Sublimaze. Reproduction studies in rats revealed a significant decrease in the pregnancy rate of all experimental groups. This decrease was most pronounced in the high dosed group (1.25 mg/kg — 12.5X human dose) in which one of twenty animals became pregnant.

Pregnancy

Category C

Sublimaze has been shown to impair fertility and to have an embryocidal effect in rats when given in doses 0.3 times the upper human dose for a period of 12 days. No evidence of teratogenic effects have been observed after administration of Sublimaze to rats. There are no adequate and well-controlled studies in pregnant women. Sublimaze should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

There are insufficient data to support the use of Sublimaze in labor and delivery. Therefore, such use is not recommended.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sublimaze is administered to a nursing woman.

Pediatric Use

The safety and efficacy of Sublimaze in children under two years of age have not been established.

Rare cases of unexplained clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery which included the combined use of fentanyl, pancuronium and atropine. A direct cause and effect relationship between the combined use of these drugs and the reported cases of methemoglobinemia has not been established.

Adverse Reactions

As with other narcotic analgesics, the most common serious adverse reactions reported to occur with Sublimaze (fentanyl citrate) are respiratory depression, apnea, rigidity, and bradycardia; if these remain untreated, respiratory arrest, circulatory depression or cardiac arrest could occur. Other adverse reactions that have been reported are hypertension, hypotension, dizziness, blurred vision, nausea, emesis, diaphoresis, pruritus, urticaria, laryngospasm and anaphylaxis.

It has been reported that secondary rebound respiratory depression may occasionally occur postoperatively. Patients should be monitored for this possibility and appropriate countermeasures taken as necessary.

When a tranquilizer is used with Sublimaze, the following adverse reactions can occur: chills and/or shivering, restlessness, and postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression); extrapyramidal symptoms (dystonia, akathisia, and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with anti-parkinson agents. Postoperative drowsiness is also frequently reported following the use of neuroleptics with Sublimaze.

Cases of cardiac dysrhythmias, cardiac arrest, and death have been reported following the use of Sublimaze with a neuroleptic agent.

Drug Abuse and Dependence

Sublimaze (fentanyl citrate) is a Schedule II controlled drug substance that can produce drug dependence of the morphine type and therefore has the potential for being abused.

Overdosage

Manifestations

The manifestations of Sublimaze (fentanyl citrate) overdosage are an extension of its pharmacologic actions (see CLINICAL PHARMACOLOGY) as with other opioid analgesics. The intravenous LD50 of Sublimaze is 3 mg/kg in rats, 1 mg/kg in cats, 14 mg/kg in dogs and 0.03 mg/kg in monkeys.

Treatment

In the presence of hypoventilation or apnea, oxygen should be administered and respiration should be assisted or controlled as indicated. A patent airway must be maintained; an oropharyngeal airway or endotracheal tube might be indicated. If depressed respiration is associated with muscular rigidity, an intravenous neuromuscular blocking agent might be required to facilitate assisted or controlled respiration. The patient should be carefully observed for 24 hours; body warmth and adequate fluid intake should be maintained. If hypotension occurs and is severe or persists, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy. A specific narcotic antagonist such as nalorphine, levallorphan or naloxone should be available for use as indicated to manage respiratory depression. This does not preclude the use of more immediate countermeasures. The duration of respiratory depression following overdosage of Sublimaze may be longer than the duration of narcotic antagonist action. Consult the package insert of the individual narcotic antagonists for details about use.

Sublimaze Dosage and Administration

50 mcg = 0.05 mg = 1 ml

Dosage should be individualized. Some of the factors to be considered in determining the dose are age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used and the surgical procedure involved. Dosage should be reduced in elderly or debilitated patients (see PRECAUTIONS).

Vital signs should be monitored routinely.

I.

Premedication — Premedication (to be appropriately modified in the elderly, debilitated and those who have received other depressant drugs) — 50 to 100 mcg (0.05 to 0.1 mg) (1 to 2 ml) may be administered intramuscularly 30 to 60 minutes prior to surgery.

II.

Adjunct to General Anesthesia — See Dosage Range Chart

III.

Adjunct to Regional Anesthesia - 50 to 100 mcg (0.05 to 0.1 mg) (1 to 2 ml) may be administered intramuscularly or slowly intravenously, over one to two minutes, when additional analgesia is required.

IV.

Postoperatively (recovery room) - 50 to 100 mcg (0.05 to 0.1 mg) (1 to 2 ml) may be administered intramuscularly for the control of pain, tachypnea and emergence delirium. The dose may be repeated in one to two hours as needed.

Usage in Children: For induction and maintenance in children 2 to 12 years of age, a reduced dose as low as 2 to 3 mcg/kg is recommended.

DOSAGE RANGE CHART

TOTAL DOSAGE
Low Dose — 2 mcg/kg (0.002 mg/kg) (0.04 ml/kg) Sublimaze. Sublimaze in small doses is most useful for minor, but painful, surgical procedures. In addition to the analgesia during surgery, Sublimaze may also provide some pain relief in the immediate postoperative period.	Moderate Dose — 2 to 20 mcg/kg (0.002 to 0.02 mg/kg) (0.04 to 0.4 ml/kg) Sublimaze. Where surgery becomes more major, a larger dose is required. With this dose, in addition to adequate analgesia, one would expect to see some abolition of the stress response. However, respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential.	High Dose — 20 to 50 mcg/kg (0.02 to 0.05 mg/kg) (0.4 to 1 ml/kg) Sublimaze. During open heart surgery and certain more complicated neurosurgical and orthopedic procedures where surgery is more prolonged, and in the opinion of the anesthesiologist, the stress response to surgery would be detrimental to the well being of the patient, dosages of 20 to 50 mcg/kg (0.02 to 0.05 mg) (0.4 to 1 ml) of Sublimaze with nitrous oxide/oxygen have been shown to attenuate the stress response as defined by increased levels of circulating growth hormone, catecholamine, ADH and prolactin. When dosages in this range have been used during surgery, postoperative ventilation and observation are essential due to extended postoperative respiratory depression. The main objective of this technique would be to produce "stress free" anesthesia.

 

DOSAGE RANGE CHART

MAINTENANCE DOSAGE
Low Dose — 2 mcg/kg (0.002 mg/kg) (0.04 ml/kg) Sublimaze. Additional dosages of Sublimaze are infrequently needed in these minor procedures.	Moderate Dose — 2 to 20 mcg/kg (0.002 to 0.02 mg/kg) (0.04 to 0.4 ml/kg) Sublimaze. 25 to 100 mcg (0.025 to 0.1 mg) (0.5 to 2.0 ml) may be administered intravenously or intramuscularly when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia.	High Dose — 20 to 50 mcg/kg (0.02 to 0.05 mcg/kg) (0.4 to 1.0 ml/kg) Sublimaze. Maintenance dosage (ranging from 25 mcg (0.025 mg) (0.5 ml) to one half the initial loading dose) will be dictated by the changes in vital signs which indicate stress and lightening of analgesia. However, the additional dosage selected must be individualized especially if the anticipated remaining operative time is short.

As a General Anesthetic

When attenuation of the responses to surgical stress is especially important, doses of 50 to 100 mcg/kg (0.05 to 0.1 mg/kg) (1 to 2 ml/kg) may be administered with oxygen and a muscle relaxant. This technique has been reported to provide anesthesia without the use of additional anesthetic agents. In certain cases, doses up to 150 mcg/kg (0.15 mg/kg) (3 ml/kg) may be necessary to produce this anesthetic effect. It has been used for open heart surgery and certain other major surgical procedures in patients for whom protection of the myocardium from excess oxygen demand is particularly indicated, and for certain complicated neurological and orthopedic procedures.

As noted above, it is essential that qualified personnel and adequate facilities be available for the management of respiratory depression.

See WARNINGS and PRECAUTIONS for use of Sublimaze (fentanyl citrate) with other CNS depressants, and in patients with altered response.

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

How is Sublimaze Supplied

Sublimaze (fentanyl citrate) Injection is available as:

NDC 11098-030-02	50 mcg/ml of fentanyl base,	2 ml ampoules in packages of 10
NDC 11098-030-05	50 mcg/ml of fentanyl base,	5 ml ampoules in packages of 10
NDC 11098-030-10	50 mcg/ml of fentanyl base,	10 ml ampoules in packages of 5
NDC-11098-030-20	50 mcg/ml of fentanyl base,	20 ml ampoules in packages of 5

STORAGE

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. PROTECT FROM LIGHT.

TAYLOR PHARMACEUTICALS

AN AKORN COMPANY

Decatur, IL 62522

AFCA0N Rev. 08/05

Sublimaze  fentanyl citrate  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 11098-030 Route of Administration INTRAVENOUS, INTRAMUSCULAR DEA Schedule CII

INGREDIENTS Name (Active Moiety) Type Strength fentanyl citrate (fentanyl) Active 50 MICROGRAM  In 1 MILLILITER sodium hydroxide Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 11098-030-02 10 AMPULE In 1 PACKAGE contains a AMPULE 1 2 mL (MILLILITER) In 1 AMPULE This package is contained within the PACKAGE (11098-030-02) 2 11098-030-05 10 AMPULE In 1 PACKAGE contains a AMPULE 2 5 mL (MILLILITER) In 1 AMPULE This package is contained within the PACKAGE (11098-030-05) 3 11098-030-10 5 AMPULE In 1 PACKAGE contains a AMPULE 3 10 mL (MILLILITER) In 1 AMPULE This package is contained within the PACKAGE (11098-030-10) 4 11098-030-20 5 AMPULE In 1 PACKAGE contains a AMPULE 4 20 mL (MILLILITER) In 1 AMPULE This package is contained within the PACKAGE (11098-030-20)

Revised: 04/2008Taylor Pharmaceuticals

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Care Decongestant Oral Liquid

1. Name Of The Medicinal Product

Galsud Linctus or Care Decongestant Oral Liquid

2. Qualitative And Quantitative Composition

Active Ingredient:

Pseudoephedrine hydrochloride BP 30.0mg (Per 5ml Dose).

For full list of excipients, see section 6.1

3. Pharmaceutical Form

Oral Liquid

A deep orange coloured liquid

4. Clinical Particulars

4.1 Therapeutic Indications

Indicated for the relief of nasal, sinus and upper respiratory congestion.

4.2 Posology And Method Of Administration

For oral administration.

Adults and children over 12 years:

Two 5ml spoonfuls three times daily.

Elderly:

Adult dose is appropriate.

4.3 Contraindications

Galsud Linctus should not be used in patients hypersensitive to pseudoephedrine, or any of the other ingredients. It is contra-indicated in patients receiving monoamine oxidase inhibitors or who have received these agents in the last two weeks. Galsud Linctus is contra-indicated in patients with severe renal impairment.

Children under 12 years of age

4.4 Special Warnings And Precautions For Use

Caution should be used in prescribing Galsud Linctus for patients with cardiovascular disease including hypertension, those with diabetes, hyper-thyroidism, raised intraoccular pressure, prostatic enlargement, bladder dysfunction or renal impairment.

Amaranth (E123) and Sunset Yellow (E110) may cause allergic reactions. Sodium Hydroxybenzoates (E215, E217 & E219) may cause allergic reactions (possibly delayed).

Galsud linctus contains 1.0 vol % ethanol (alcohol), ie, up to 154 mg per dose (10ml), equivalent to 4ml beer or 2ml of wine. Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast feeding women, children and high risk groups such as patients with liver disease or epilepsy.

Do not exceed the stated dose

Do not take with other cough and cold medicines

Do not give to children under 12 years

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Caution should be exercised with patients receiving other sympathomimetic agents, appetite suppressants or amphetamine type agents. Pseudoephedrine may antagonise the pressor effects of antihypertensive agents, severe hypertension may occur in patients receiving beta blockers. Hypertensive crisis may occur if pseudoephedrine is co-administered with MAOIs.

There may be an increased risk of arrhythmias if pseudoephedrine is given to patients receiving cardiac glycosides or tricyclic antidepressants.

The antibacterial agent furazolidone is known to cause progressive inhibition of monoamine oxidase. Although there have been no reports of hypertensive crisis, it may not be administered concurrently with Galsud Linctus.

4.6 Pregnancy And Lactation

No data are available on the use of Galsud Linctus in pregnancy. Pseudoephedrine has been used for many years without reports of serious problems.

However, caution is required and pseudoephedrine should be avoided during the first trimester of pregnancy. Pseudoephedrine has been detected in human milk with a small percentage of the total maternal dose potentially administered to the suckling infant. Although the effects on the infant have not been monitored the risk is judged to be low.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Pseudoephedrine may cause insomnia, anxiety, restlessness, tremor, tachycardia, cardiac arrhythmias, palpitations, hypertension, nausea, vomiting and headache in some patients. Skin rashes and urinary retention in men have occasionally been reported. Sleep disturbances and hallucinations have been reported rarely. A fixed drug eruption, in the form of erythematous nodular patches, has been rarely associated with pseudoephedrine. Rare cases of psychosis have occurred following misuse of pseudoephedrine.

4.9 Overdose

The symptoms of overdose include irritability, nervousness, tremor, palpitations, convulsions, urinary retention, hypertension, restlessness, difficulty in micturition, nausea, vomiting, tachycardia and cardiac arrhythmias.

Overdose should be treated by general supportive measures. In the event of gross overdose, the stomach should be emptied using airway protective gastric lavage. Respiratory and circulatory function should be maintained by supportive measures. Convulsions should be controlled using anti-convulsant therapy. Catheterisation of the bladder may be required.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Nasal decongestant for systemic use

Sympathomimetics: ATC code: R01B A02

Pseudoephedrine has direct and indirect sympathomimetic activity and is an orally effective upper respiratory tract decongestant. Pseudoephedrine is substantially less potent than ephedrine in producing both tachycardia and elevation in systolic blood pressure and considerably less potent in causing stimulation of the central nervous system.

5.2 Pharmacokinetic Properties

Pseudoephedrine hydrochloride is readily and completely absorbed from the gastro-intestinal tract. It is resistant to metabolism by monoamine oxidase and is largely excreted unchanged in the urine.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance that are additional to the presciber, which are additional to those already included in other sections of the SmPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Citric Acid Monohydrate

Sodium Hydroxybenzoates (E215, E217 & E219)

Alcohol 96%

Amaranth (E123)

Sunset Yellow FCF (E110)

Carmellose Sodium

Saccahrin Sodium

Menthol

Condensed Milk Flavour (F12516)

Orange Flavour (17.40.7040)

Glycerol

Purified Water

6.2 Incompatibilities

None stated.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Store below 25°C. Protect from light.

6.5 Nature And Contents Of Container

100ml amber glass bottle with a 28mm tamper evident child resistant closure with a low density polyethylene plug.

The 100ml bottle will be cartonned and a 5ml/2.5 ml double-ended CE marked spoon included.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Thornton & Ross Ltd

Linthwaite

Huddersfield

HD7 5QH

United Kingdom

8. Marketing Authorisation Number(S)

PL 00240/0107

9. Date Of First Authorisation/Renewal Of The Authorisation

08 July 2002

30 January 2004

10. Date Of Revision Of The Text

17/02/2010

Kalexate

Generic Name: sodium polystyrene sulfonate (Oral route)

SOE-dee-um pol-ee-STYE-reen SUL-foe-nate

Commonly used brand name(s)

In the U.S.

• Kayexalate


• Kionex

In Canada

• Pms-Sodium Polystyrene Sulfonate

Available Dosage Forms:

• Suspension


• Powder for Suspension

Therapeutic Class: Exchange Resin

Uses For Kalexate

Sodium polystyrene sulfonate is used to treat high levels of potassium in the blood, also called hyperkalemia.

This medicine is available only with your doctor's prescription.

Before Using Kalexate

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of sodium polystyrene sulfonate in the pediatric population. However, pediatric-specific problems that would limit the usefulness of this medicine in children are not expected.

This medicine should be used with caution in newborn infants who have reduced or slow bowel movements. The oral form should not be given to newborn infants.

Geriatric

No information is available on the relationship of age to the effects of sodium polystyrene sulfonate in geriatric patients.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Sorbitol

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aluminum Carbonate, Basic


• Aluminum Hydroxide


• Aluminum Phosphate


• Calcium


• Calcium Carbonate


• Dihydroxyaluminum Aminoacetate


• Dihydroxyaluminum Sodium Carbonate


• Levothyroxine


• Magaldrate


• Magnesium Carbonate


• Magnesium Hydroxide


• Magnesium Oxide


• Magnesium Trisilicate

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bowel blockage or


• Hypokalemia (low potassium in the blood)—Should not be used in patients with these conditions.

• Congestive heart failure, severe or


• Edema (fluid retention) or


• Heart rhythm problems (e.g., arrhythmia, QT prolongation) or


• Hypertension (high blood pressure), severe or


• Hypocalcemia (low calcium in the blood) or


• Hypomagnesemia (low magnesium in the blood) or


• Stomach or bowel problems (e.g., bleeding, colitis, constipation, perforation)—Use with caution. May make these conditions worse.

Proper Use of sodium polystyrene sulfonate

This section provides information on the proper use of a number of products that contain sodium polystyrene sulfonate. It may not be specific to Kalexate. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine comes as a liquid suspension and as a powder that is mixed with water or syrup. If you or your child are not able to swallow the liquid, the medicine can be put in the stomach with a special tube. Talk to your doctor if you have questions about this.

Your doctor will tell you how to mix the powder with water or syrup. Each dose of the powder must be mixed with a liquid right before you take it. Stir the powder mixture to dissolve the medicine. Do not store the liquid mixture to take later.

Measure the liquid suspension with a marked measuring spoon, oral syringe, or medicine cup. Shake the bottle of medicine well just before taking each dose.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (powder, suspension):
  
  • For treatment of hyperkalemia:
    
    • Adults—15 grams one to four times a day.
    
    
    • Children and infants—Dose is based on potassium blood level and must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Kalexate

It is very important that your doctor check you or your child closely to make sure that this medicine is working properly. Blood tests may be needed to check for unwanted effects.

Hypokalemia (low potassium in the blood) may occur while you are using this medicine. Check with your doctor right away if you have the following symptoms: confusion, dry mouth, increased thirst, irregular heartbeat, irritability, muscle cramps, nausea or vomiting, or shortness of breath.

If you are taking aluminum or magnesium-containing antacids or laxatives, talk to your doctor first before using them together with sodium polystyrene sulfonate. These medicines may keep sodium polystyrene sulfonate from working properly and may cause serious side effects.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Kalexate Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Rare

• Bloody vomit


• chest pain


• cough


• cough producing mucus


• difficulty with breathing


• fever or chills


• severe stomach pain


• shortness of breath


• sneezing


• sore throat


• tightness in the chest


• troubled breathing


• wheezing

Incidence not known

• Abdominal or stomach cramps or pain


• confusion


• constipation


• convulsions


• decrease in the amount of urine


• diarrhea


• dry mouth


• increased thirst


• irregular heartbeats


• loss of appetite


• muscle cramps in the hands, arms, feet, legs, or face


• nausea or vomiting


• noisy, rattling breathing


• numbness and tingling around the mouth, fingertips, or feet


• severe constipation


• swelling of the fingers, hands, feet, or lower legs


• tremor


• troubled breathing at rest


• unusual tiredness or weakness


• weight gain


• weight loss

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Dizziness


• drowsiness


• fainting


• fast, slow, or irregular heartbeat


• lightheadedness


• muscle cramps


• muscle spasms (tetany) or twitching


• pounding or rapid pulse


• seizures


• trembling

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Kalexate side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Kalexate resources

• Kalexate Side Effects (in more detail)
• Kalexate Use in Pregnancy & Breastfeeding
• Kalexate Drug Interactions
• Kalexate Support Group
• 0 Reviews for Kalexate - Add your own review/rating

• Kalexate Concise Consumer Information (Cerner Multum)


• Sodium Polystyrene Sulfonate Prescribing Information (FDA)


• Sodium Polystyrene Sulfonate Professional Patient Advice (Wolters Kluwer)


• Sodium Polystyrene Sulfonate Monograph (AHFS DI)


• Kayexalate Prescribing Information (FDA)


• Kayexalate Powder MedFacts Consumer Leaflet (Wolters Kluwer)


• Kionex Prescribing Information (FDA)

Compare Kalexate with other medications

• Hyperkalemia

Polocaine Injection

Dosage Form: injection

451105A/Revised: May 2008

Polocaine®(Mepivacaine Hydrochloride Injection, USP)

Polocaine®-MPF (Mepivacaine Hydrochloride Injection, USP)

THESE SOLUTIONS ARE NOT INTENDED FOR SPINAL ANESTHESIA OR DENTAL USE

Rx only

DESCRIPTION:

Mepivacaine hydrochloride is 2-Piperidinecarboxamide, N-(2, 6-dimethylphenyl)-1-methyl-, monohydrochloride and has the following structural formula:

The molecular formula is C15H22N2O • HCl.

            It is a white, crystalline odorless, powder, soluble in water, but very resistant to both acid and alkaline hydrolysis.

            Mepivacaine hydrochloride is a local anesthetic available as sterile isotonic solutions (clear, colorless) in concentrations of 1%, 1.5% and 2% for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks.

            Mepivacaine hydrochloride is related chemically and pharmacologically to the amide-type local anesthetics.  It contains an amide linkage between the aromatic nucleus and the amino group.

Composition of Available Solutions*

	1% Single Dose 30 mL Vial mg/mL	1% Multiple Dose 50 mL Vial mg/mL	1.5% Single Dose 30 mL Vial mg/mL	2% Single Dose 20 mL Vial mg/mL	2% Multiple Dose 50 mL Vial mg/mL
Mepivacaine hydrochloride	10	10	15	20	20
Sodium chloride	6.6	7	5.6	4.6	5
Potassium chloride	0.3		0.3	0.3
Calcium chloride	0.33		0.33	0.33
Methylparaben		1			1
*In Water for Injection

 

            The pH of the solution is adjusted between 4.5 and 6.8 with sodium hydroxide or hydrochloric acid.

CLINICAL PHARMACOLOGY:

Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers.  Clinically, the order of loss of nerve function is as follows: pain, temperature, touch, proprioception, and skeletal muscle tone.

            Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems.  At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal.  However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block and ultimately to cardiac arrest.  In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure.

            Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both.  Apparent central stimulation is manifested as restlessness, tremors, and shivering, progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest.  However, the local anesthetics have a primary depressant effect on the medulla and on higher centers.  The depressed stage may occur without a prior excited stage.

            A clinical study using 15 mL of 2% epidural mepivacaine at the T 9-10 interspace in 62 patients, 20-79 years of age, demonstrated a 40% decrease in the amount of mepivacaine required to block a given number of dermatomes in the elderly (60-79 years, N=13) as compared to young adults 20-39 years).  

            Another study using 10 mL of 2% lumbar epidural mepivacaine in 161 patients, 19-75 years of age, demonstrated a strong inverse relationship between patient age and the number of dermatomes blocked per cc of mepivacaine injected.

 

 

Pharmacokinetics

The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5mcg/mL) usually reduces the rate of absorption and plasma concentration of mepivacaine, however, it has been reported that vasoconstrictors do not significantly prolong anesthesia with mepivacaine.

            Onset of anesthesia with mepivacaine is rapid, the time of onset for sensory block ranging from about 3 to 20 minutes depending upon such factors as the anesthetic technique, the type of block, the concentration of the solution, and the individual patient. The degree of motor blockade produced is dependent on the concentration of the solution. A 0.5% solution will be effective in small superficial nerve blocks while the 1% concentration will block sensory and sympathetic conduction without loss of motor function.  The 1.5% solution will provide extensive and often complete motor block and the 2% concentration of mepivacaine hydrochloride will produce complete sensory and motor block of any nerve group.

            The duration of anesthesia also varies depending upon the technique and type of block, the concentration, and the individual.  Mepivacaine will normally provide anesthesia which is adequate for 2 to 2½ hours of surgery.

            Local anesthetics are bound to plasma proteins in varying degrees.  Generally, the lower the plasma concentration of drug, the higher the percentage of drug bound to plasma.

            Local anesthetics appear to cross the placenta by passive diffusion.  The rate and degree of diffusion is governed by the degree of plasma protein binding, the degree of ionization, and the degree of lipid solubility.  Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer.  Mepivacaine is approximately 75% bound to plasma proteins.  The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug.  Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation.

            Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.

            Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient.  The half-life of mepivacaine in adults is 1.9 to 3.2 hours and in neonates 8.7 to 9 hours.

            Mepivacaine, because of its amide structure, is not detoxified by the circulating plasma esterases.  It is rapidly metabolized, with only a small percentage of the anesthetic (5 percent to 10 percent) being excreted unchanged in the urine.  The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile as metabolites.  Most of the metabolized mepivacaine is probably resorbed in the intestine and then excreted into the urine since only a small percentage is found in the feces.  The principal route of excretion is via the kidney.  Most of the anesthetic and its metabolites are eliminated within 30 hours.  It has been shown that hydroxylation and N-demethylation, which are detoxification reactions, play important roles in the metabolism of the anesthetic.  Three metabolites of mepivacaine have been identified from human adults: two phenols, which are excreted almost exclusively as their glucuronide conjugates, and the N-demethylated compound (2’,6’-pipecoloxylidide). 

            Mepivacaine does not ordinarily produce irritation or tissue damage, and does not cause methemoglobinemia when administered in recommended doses and concentrations.

INDICATIONS AND USAGE:

POLOCAINE (Mepivacaine HCl Injection, USP), is indicated for production of local or regional analgesia and anesthesia by local infiltration, peripheral nerve block techniques, and central neural techniques including epidural and caudal blocks.

            The routes of administration and indicated concentrations for mepivacaine are:

  

local infiltration                           0.5% (via dilution) or 1%

peripheral nerve blocks	1% and 2%
epidural block	1%, 1.5%, 2%
caudal block	1%, 1.5%, 2%

            See DOSAGE AND ADMINISTRATION for additional information.  Standard textbooks should be consulted to determine the accepted procedures and techniques for the administration of mepivacaine.

CONTRAINDICATIONS:

Mepivacaine is contraindicated in patients with a known hypersensitivity to it or to any local anesthetic agent of the amide-type or to other components of mepivacaine solutions.

WARNINGS:

LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER INSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES. (See also  ADVERSE REACTIONS and PRECAUTIONS.)  DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE, AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH.

            Local anesthetic solutions containing antimicrobial preservatives (ie, those supplied in multiple-dose vials) should not be used for epidural or caudal anesthesia because safety has not been established with regard to intrathecal injection, either intentionally or inadvertently, of such preservatives.

            It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection.  However, a negative aspiration does not ensure against an intravascular or subarachnoid injection.

            Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics.

            Mepivacaine with epinephrine or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur.  Likewise, solutions of mepivacaine containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result.

            Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection.

            Mixing or the prior or intercurrent use of any local anesthetic with mepivacaine cannot be recommended because of insufficient data on the clinical use of such mixtures.

PRECAUTIONS:

General

The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies.  Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use (see WARNINGS and ADVERSE REACTIONS).  During major regional nerve blocks, the patient should have IV fluids running via an indwelling catheter to assure a functioning intravenous pathway.  The lowest dosage of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects.  Injections should be made slowly, with frequent aspirations before and during the injection to avoid intravascular injection.  Current opinion favors fractional administration with constant attention to the patient, rather than rapid bolus injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques.  An intravascular injection is still possible even if aspirations for blood are negative.

            During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given. When using a “continuous” catheter technique, test doses should be given prior to both the original and all reinforcing doses, because plastic tubing in the epidural space can migrate into a blood vessel or through the dura.  When the clinical conditions permit, an effective test dose should contain epinephrine (10 mcg to 15 mcg have been suggested) to serve as a warning of unintended intravascular injection.  If injected into a blood vessel, this amount of epinephrine is likely to produce an “epinephrine response” within 45 seconds, consisting of an increase of pulse and blood pressure, circumoral pallor, palpitations, and nervousness in the unsedated patient.  The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart rate should be monitored for a heart rate increase.  The test dose should also contain 45 mg to 50 mg of mepivacaine hydrochloride to detect an unintended intrathecal administration.  This will be evidenced within a few minutes by signs of spinal block (eg, decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk).

            Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites or to slow metabolic degradation.  Tolerance to elevated blood levels varies with the status of the patient.  Debilitated, elderly patients, and acutely ill patients should be given reduced doses commensurate with their age and physical status.  Local anesthetics should also be used with caution in patients with severe disturbances of cardiac rhythm, shock, heart block, or hypotension.

            Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs, and the patient’s state of consciousness should be performed after each local anesthetic injection.  It should be kept in mind at such times that restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity.

            Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, penis. Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response.  Ischemic injury or necrosis may result.

            Mepivacaine should be used with caution in patients with known allergies and sensitivities.

            Because amide-type local anesthetics such as mepivacaine are metabolized by the liver and excreted by the kidneys, these drugs, especially repeat doses, should be used cautiously in patients with hepatic and renal disease.  Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations.  Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these drugs.

            Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are employed in patients during or following the administration of potent inhalation anesthetics.  In deciding whether to use these products concurrently in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. 

            Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia.  Because it is not known whether amide-type local anesthetics may trigger this reaction and because the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available.  Early unexplained signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation.  Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s), and institution of treatment, including oxygen therapy, indicated supportive measures, and dantrolene.  (Consult dantrolene sodium intravenous package insert before using.)

Use in Head and Neck Area

Small doses of local anesthetics injected into the head and neck area may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses.  The injection procedures require the utmost care.

            Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported.  These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation.  Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed.  Resuscitative equipment and personnel for treating adverse reactions should be immediately available.  Dosage recommendations should not be exceeded.

Information for Patients

When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia.  Also, when appropriate, the physician should discuss other information including adverse reactions listed in this package insert.

Clinically Significant Drug Interactions

The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension.  Concurrent use of these agents should generally be avoided.  In situations when concurrent therapy is necessary, careful patient monitoring is essential. 

            Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.

            Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term studies in animals of most local anesthetics including mepivacaine to evaluate the carcinogenic potential have not been conducted.  Mutagenic potential or the effect on fertility have not been determined.  There is no evidence from human data that mepivacaine may be carcinogenic or mutagenic or that it impairs fertility.

Pregnancy Category C

Animal reproduction studies have not been conducted with mepivacaine.  There are no adequate and well-controlled studies in pregnant women of the effect of mepivacaine on the developing fetus.  Mepivacaine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.  This does not preclude the use of mepivacaine at term for obstetrical anesthesia or analgesia (see Labor and Delivery).

            Mepivacaine has been used for obstetrical analgesia by the epidural, caudal, and paracervical routes without evidence of adverse effects on the fetus when no more than the maximum safe dosages are used and strict adherence to technique is followed.

Labor and Delivery

Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity (see CLINICAL PHARMACOLOGY, Pharmacokinetics).  The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration.  Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function.

            Maternal hypotension has resulted from regional anesthesia.  Local anesthetics produce vasodilation by blocking sympathetic nerves.  Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure.  The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable.

            Epidural, paracervical, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts.  In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation.  Epidural anesthesia has been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function.  The use of obstetrical anesthesia may increase the need for forceps assistance.

            The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life.  The long-term significance of these observations is unknown.

            Fetal bradycardia may occur in 20 to 30 percent of patients receiving para-cervical block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis.  Fetal heart rate should always be monitored during paracervical anesthesia.  Added risk appears to be present in prematurity, postmaturity, toxemia of pregnancy, and fetal distress.  The physician should weigh the possible advantages against dangers when considering paracervical block in these conditions.  Careful adherence to recommended dosage is of the utmost importance in obstetrical paracervical block.  Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection.

            Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth which correlates with high local anesthetic serum levels and usually manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication.

            Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid.  The recommended maximum dose of the local anesthetic should not be exceeded. Injection should be made slowly and with frequent aspiration.  Allow a five-minute interval between sides.

            It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients.  To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and the gravid uterus displaced to the left.

Nursing Mothers

It is not known whether local anesthetic drugs are excreted in human milk.  Because many drugs are excreted in human milk, caution should be exercised when local anesthetics are administered to a nursing woman.

Pediatric Use

Guidelines for the administration of mepivacaine to pediatric patients are presented in DOSAGE AND ADMINISTRATION.

Geriatric Use

Clinical studies and other reported clinical experience indicates that use of the drug in elderly patients requires a decreased dosage (see CLINICAL PHARMACOLOGY, PRECAUTIONS, General, and DOSAGE AND ADMINISTRATION).

            Mepivacaine and mepivacaine metabolites are 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.

ADVERSE REACTIONS:

Reactions to mepivacaine are characteristic of those associated with other amide-type local anesthetics.  A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, inadvertent intravascular injection, or slow metabolic degradation.

Systemic

The most commonly encountered acute adverse experiences which demand immediate countermeasures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose related and due to high plasma levels which may result from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution.  In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea (“Total or High Spinal”).  Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur.  This may lead to secondary cardiac arrest if untreated.  Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance.

Central Nervous System Reactions

These are characterized by excitation and/or depression.  Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction.  This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest.  Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils.

            The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered.  In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations.

Cardiovascular Reactions

High doses or, inadvertent intravascular injection, may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension (or sometimes hypertension), bradycardia, ventricular arrhythmias, and possibly cardiac arrest (see WARNINGS, PRECAUTIONS, and OVERDOSAGE).

Allergic

Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative methylparaben, contained in multiple-dose vials.  These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid-like symptomatology (including severe hypotension).  Cross sensitivity among members of the amide-type local anesthetic group has been reported.  The usefulness of screening for sensitivity has not been definitely established.

Neurologic

The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient.  Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug.

            In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur.  Subsequent adverse effects may depend partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture.  A high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia.

            Neurologic effects following epidural or caudal anesthesia may include spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities, and loss of sphincter control all of which may have slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. 

            Neurologic effects following other procedures or routes of administration may include persistent anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete or no recovery.

OVERDOSAGE:

Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution (see ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS).

Management of Local Anesthetic Emergencies

The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection.  At the first sign of change, oxygen should be administered.

            The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask.  This may prevent convulsions if they have not already occurred.

            If necessary, use drugs to control the convulsions.  A 50 mg to 100 mg bolus IV injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems and facilitate ventilation.  A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress central nervous system, respiratory, and cardiac function, add to postictal depression and may result in apnea.  Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use.  Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated.  Supportive treatment of circulatory depression may require administration of intravenous fluids, and when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force).

            Endotracheal intubation, employing drugs and techniques familiar to the clinician may be indicated after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of patent airway or if prolonged ventilatory support (assisted or controlled) is indicated.

            Recent clinical data from patients experiencing local anesthetic induced  convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis within a minute of the onset of convulsions.  These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest.

            If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis, plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest.  Respiratory abnormalities, including apnea, may occur.  Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted.  If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted and maintained for a prolonged period if necessary. Recovery has been reported after prolonged resuscitative efforts.

            The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus.  Therefore, during treatment of systemic toxicity, maternal hypotension, or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels should be accomplished.

            The mean seizure dosage of mepivacaine in rhesus monkeys was found to be 18.8 mg/kg with mean arterial plasma concentration of 24.4 mcg/mL.  The intravenous and subcutaneous LD50 in mice is 23 mg/kg to 35 mg/kg and 280 mg/kg respectively.

DOSAGE AND ADMINISTRATION:

The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance and the physical condition of the patient.  The smallest dose and concentration required to produce the desired result should be administered.  Dosages of mepivacaine hydrochloride should be reduced for elderly and debilitated patients and patients with cardiac and/or liver disease.  The rapid injection of a large volume of local anesthetic solution should be avoided and fractional doses should be used when feasible.

            For specific techniques and procedures, refer to standard textbooks.

            The recommended single adult dose (or the total of a series of doses given in one procedure) of mepivacaine hydrochloride for unsedated, healthy, normal-sized individuals should not usually exceed 400 mg.  The recommended dosage is based on requirements for the average adult and should be reduced for elderly or debilitated patients.

            While maximum doses of 7 mg/kg (550 mg) have been administered without adverse effect, these are not recommended, except in exceptional circumstances and under no circumstances should the administration be repeated at intervals of less than 1½ hours.  The total dose for any 24-hour period should not exceed 1,000 mg because of a slow accumulation of the anesthetic or its derivatives or slower than normal metabolic degradation or detoxification with repeat administration (see CLINICAL PHARMACOLOGY and PRECAUTIONS).

            Pediatric patients tolerate the local anesthetic as well as adults.  However, the pediatric dose should be carefully measured as a percentage of the total adult dose based on weight, and should not exceed 5 mg/kg to 6 mg/kg (2.5 mg/lb to 3 mg/lb) in pediatric patients, especially those weighing less than 30 lbs.  In pediatric patients under 3 years of age or weighing less than 30 lbs concentrations less than 2% (eg, 0.5% to 1.5%) should be employed.

            Unused portions of solutions not containing preservatives, ie, those supplied in single-dose vials, should be discarded following initial use.

            This product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.  Solutions which are discolored or which contain particulate matter should not be administered.

Recommended Concentrations and Doses of Mepivacaine Hydrochloride

Procedure	Concentration	mL	Total Dose	mg	Comments
Cervical,	1%	5-40		50-400	Pudendal block:
brachial,					one half of total
intercostal,					dose injected
pudendal	2%	5-20		100-400	each side.
nerve block
Transvaginal	1%	up to 30		up to 300	One half of total
block		(both sides)		(both sides)	dose injected
(paracervical					each side.  See
plus pudendal)					PRECAUTIONS.
Paracervical	1%	up to 20		up to 200	One half of total
block		(both sides)		(both sides)	dose injected each
					side.  This is maxi-