Bupivacaine Hydrochloride

Bupivacaine Hydrochloride

5mg/ml Solution for Spinal Injection

Drug Category: Local Anesthetic

Brand Name: Sensorcaine 0.5% Heavy

Clinical Particulars

Therapeutic Indications:

Spinal anesthesia for surgery, e.g. urological surgery and surgery on the lower limbs lasting 2-3 hours, abdominal surgery lasting 45-60 minutes.

Dosage and method of administrations:

Bupivacaine hydrochloride Spinal Heavy should only be used by clinicians with experience of regional anesthesia or under their supervision. The lowest possible dose for adequate anesthesia should be used.

The doses given below are guides for adults and the dosage should be adjusted to the individual patients.

The dose should be reduced in elderly patients and patients in late stages of pregnancy.

Indication	Dose mL	Dose mg	Time to onset of effect in minutes (approx.)	Duration of effect in hours (approx.)
Urological surgery Surgery on lower limbs, including hip surgery Abdominal surgery (including cesarean section)	1.5-3 ml 2-4 ml 2-4 ml	7.5-15 mg 10-20 mg 10-20 mg	5-8 min 5-8 min 5-8 min	2-3 hours 2-3 hours 45-60 min

The recommended injection site is the L₃-L₄ intervertebral space. There is currently no experience of doses higher than 20 mg. A spinal injection is given only after the subarachnoid space has been clearly identified by means of lumbar puncture (clear cerebrospinal fluid runs out via the spinal needle or is seen on aspiration). In the event of unsuccessful anesthesia, a new attempt to administer the drug should only be made by injecting at a different level and with a smaller volume. One cause of lack of effect may be poor intrathecal distribution of the drug, and this can be helped by altering the patient's position.

Contraindications:

Hypersensitivity to local anesthetics of the amide type or to other components of the product. Diseases of the central nervous system (e.g. meningitis, poliomelitis, intracranial hemorrhage). Local pyogenic infection at or adjacent to the injection site. Spinal stenosis and active disease (e.g. spondylitis, tumor) or trauma (e.g. fracture of the spine). Septicemia, pernicious anemia with subacute degeneration of the spinal cord. Spinal anesthesia should not be given to patients in shock. Nor should spinal anesthesia be given to patients with coagulation disorders or to patients receiving ongoing anticoagulation treatment.

Special warning and precaution for use:

One should be aware that spinal anesthesia can sometimes lead to major blocks, with paralysis of intercostal muscles and the diaphragm, especially in pregnant women.

Caution should be exercised in patients with degree II or III-AV block since local anesthetics can lower the conduction capacity of the myocardium. Elderly patients and patients with severe hepatic disease, severely impaired renal function or in generally reduced general condition also require special attention.

Patients treated with class III anti-arrhythmic drugs (e.g. amiodarone) should be closely observed and ECG monitoring should be considered, since the cardiac effects of bupivacaine and class III anti-arrhythmic drugs can be addictive.

Like all local anesthetic drugs, bupivacaine can cause acute central nervous and cardiovascular toxic effects in cases of use leading to high concentrations in the blood. This applies particularly after inadvertent intravascular administration.

Ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death have been reported in association with high systemic concentrations of bupivacaine. However, with doses normally used for spinal anesthesia high systemic concentrations are uncommon.

An uncommon, but dangerous, side effect in spinal anesthesia is extensive or total spinal blockade, which results in cardiovascular depression and respiratory depression. The cardiovascular depression is caused by extensive sympathetic blockade, which can result in hypotension and bradycardia, or even cardiac arrest. Respiratory depression can be caused by blockade of the innervation of the respiratory muscles, including the diaphragm. There is an increased risk of extensive or total spinal blockade in elderly patients and patients in late stages of pregnancy. The dose should therefore be reduced for these patients.

Spinal anesthesia can lead to a fall in blood pressure and bradycardia. The risk can be reduced by means of intravenous administration of crystalloid or colloid solution. A fall in blood pressure should be treated immediately, for example with ephedrine 5-10mg intravenously, repeated as required.

In rare cases spinal anesthesia can cause neurological damage, resulting in paresthesia, anesthesia, motor weakness and paralysis. Neurological disorders, such as multiple sclerosis, hemiplegia, paraplegia and neuromuscular disturbances are not thought to be adversely affected by spinal anesthesia, but caution should be exercised.

Interactions with other medical products and other forms of interactions:

Bupivacaine should be use with caution with other local anesthesia or drugs that are structurally similar to local anesthetics, i.e. class IB anti-arrhythmic drugs, as the toxic effects are additive.

No specific interaction studies with local anesthesia and class III anti-arrhythmic drugs (e.g. amiodarone) have been carried out, but caution is recommended (see Special warning and special precautions for use).

Pregnancy and Lactation:

Pregnancy

No known risks for the fetus from use during pregnancy. However, note that the dose should be reduced for patients in late stages of pregnancy (see Special warning and special precautions for use).

Lactation

Bupivacaine passes into breast milk, but the risk of this affecting the child appears unlikely with therapeutic doses.

Effects on ability to drive and use machines:

Depending on the dose and method of administration, bupivacaine can have a transient effect on movement and coordination.

Undesirable effects:

Undesirable effects caused by the product itself can be difficult to distinguish form the physiological effects of the nerve block (e.g. fall in blood pressure, bradycardia, temporary urinary retention), events caused directly by the needle puncture (e.g. spinal hematoma) or caused indirectly by the needle puncture (e.g. meningitis, epidural abscess) or events associated with leakage of cerebrospinal fluid ( e.g. post lumbar puncture headache).

Very common (>1/10)	General: Nausea Circ.: Hypotension, bradycardia
Common (>1/100)	CNS: Post lumbar puncture headache GI: Vomiting Genitourinary: Urinary retention, urinary incontinence
Uncommon (1/100-1/1000)	CNS: Paresthesia, paresia, dysesthesia Musculoskel.: Muscle weakness, back pain
Rare (<1/1000)	Circ.: Cardiac arrest General: Allergic reactions, anaphylactic shock CNS: Accidental total spinal blockade, paraplegia, paralysis, neurophathy, arachnoiditis Airways: Respiratory depression

Overdose:

Bupivacaine can cause acute toxic effects of a central nervous and cardiovascular nature if it is given in high doses, especially if it is administered intravascularly. However, the dose used in spinal anesthesia is low (≤ 20% of the dose used for epidural anesthesia) and thus the risk of overdosage is unlikely. In cases of concomitantly administration with other local anesthetics, however, systemic toxic effects may occur, ass the toxic effects are additive.

Treatment of complications

In cases of total spinal blockade adequate ventilation must be ensured (patent airways, oxygen, intubation and controlled ventialtion if necessary). If there is a fall in blood pressure a vasopressor (preferably with an inotropic effect) should be given, e.g. ephedrine 5-10mg intravenously.

If signs of acute systemic toxicity occur the administration of local anesthesia must be stopped immediately. Treatment must be given to maintain good ventilation, oxygenation and circulation. Oxygen must always be given, and assisted ventilation if necessary. If convulsions do not cease spontaneously within 15-20 seconds, theopentone sodium 1-3 mg/kg should be given intravenously to facilitate ventilation or diazepam 0.1 mg/kg intravenously ( acts rather more slowly). Prolonged seizures jeopardize the patient's respiration and oxygenation. Injection of muscle relaxants (e.g. suxamethonium 1mg/kg) creates more favourable conditions for ventilation and oxygenation of the patient, but requires experience of tracheal intubation and controlled ventilation. In cases of a fall in blood pressure/bradycardia, a vasopressor should be given (e.g. ephedrine 5-10 mg intravenously, which may be repeated after 2-3 minutes). In the event of circulatory arrest, cardiopulmonary resuscitation should be instituted immediately. It is important to maintain good oxygenation, respiration and circulation, and to treat acidosis.

Children must be given doses in proportion to their age and body weight for treatment of systemic toxicity.

Pharmacological Properties

Pharmacodynamic Properties

Bupivacaine hydrochloride spinal heavy contains bupivacaine, which is a long-acting local anesthetic of the amide type. Bupivacaine reversibly blocks impulse conduction in the nerves by inhibiting the transport of sodium ions through the nerve membrane. Similar effects can also be seen on excitatory membranes in the brain and myocardium.

Bupivacaine hydrochloride spinal heavy is intended for hyperbaric spinal anesthesia. The relative density of the solution for injection is 1.026 at 20^oC (equivalent to 1.021 at 37^oC) and the initial distribution into the subarachnoid space is markedly influenced by gravity.

For administration into the spine, a small dose is given, which gives a relatively low concentration and short duration of effects. Bupivacaine hydrochloride spinal (without glucose) produces a less predictable block, but with a longer duration of effects than bupivacaine hydrochloride spinal heavy (with glucose).

Pharmacokinetic Properties:

Bupivacaine is very liposoluble with an oil/water distribution coefficient of 27.5.

Bupivacaine displays complete and bi-phasic absorption from the subarachnoid space, with half-lives for the two phases of approx. 50 and approx. 400 minutes, with large variations. The slow absorption phase is the rate-determining factor in the elimination of bupivacaine, which explains why the apparent half-life is longer than after intravenous administration.

Absorption form the subarachnoid space is relatively slow, which, in combination with the low dose required a spinal anesthesia, gives relatively low plasma concentration (approx. 0.4 mg/mL per 100 mg injected).

After intravenous administration, total plasma clearances is approx. 0.58 L/min, the volume of distribution in steady state is approx. 73 L, the elimination half-life is 2.7 hours, and the hepatic extraction ration is approx. 0.40. Bupivacaine is metabolized almost completely in the liver, predominantly through aromatic hydroxylation to 4-hydorxybupivacaine and N-dealkylation to PPX, both of which are mediated by cytochrome P450 3A4. Clearance is thus depended on hepatic perfusion and the activity of the metabolizing enzyme.

Bupivacaine crosses the placenta and the concentration of free bupivacaine is the same in the the mother and the fetus. However, the total plasma concentration is lower in the fetus, which has a lower degree of protein binding.

Pharmaceutical Particulars

Incompatibilities:

Additions to spinal solutions are not recommended.

Shelf-Life:

Please refer to the expiration date.

The solution must be used as soon as possible after the container has been opened.

Storage:

Store at a temperature not exceeding above 25^oC. Do not freeze.

MEFENAMIC ACID

MEFENAMIC ACID

500mg Capsule

250mg Capsule

50mg/5ml Suspension

DRUG CATEGORY: Analgesic/Antipyretic, Non Steroidal Anti-inflammatory

BRAND NAME: Ponstan®

DESCRIPTION:

Mefenamic acid is N-(2,3,-xylyl)-anthranilic acid. It is an orally active analgesic agent. It is a white powder with a melting point of 230-231^oC, molecular weight of 241.28, and water solubility of 0.0004% at pH 7.1.

THERAPEUTIC INDICATIONS

Mefenamic acid is indicated for:

1. The symptomatic relief of rheumatoid arthritis (including Still's Disease), osteoarthritis, and pain including muscular, traumatic and dental pain, headaches of most etiology, post-operative and postpartum pain.
2. The symptomatic relief of primary dysmenorrhea.
3. Menorrhagia due to dysfunctional causes or the presence of an intrauterine device (IUD) when organic pelvic pathology has been excluded.
4. Premenstrual syndrome.
5. The relief of pyrexia in pediatric patients over 6 months of age.

DOSAGE AND METHOD OF ADMINISTRATION

Undesirable effects may be minimized by using the minimum effective dose for shortest duration necessary to control symptoms.

The oral dosage form of mefenamic acid may be taken with food if gastrointestinal upset occurs.

Mild to moderate pain/rheumatoid arthritis/osteoarthritis in adults and adolescents over 14 years of age: 500mg three times daily.

Dysmenorrhea: 500mg three times daily, to be administered at the onset of menstrual pain and continued while symptoms persist according to the judgment of the physician.

Menorrhagia: 500mg three times daily, starting with the onset of bleeding and associated symptoms and continued according to the judgment of the physician.

Premenstrual syndrome: 500mg three times daily, starting with the onset of symptoms and continued until the anticipated cessation of symptoms according to the judgment of the physician.

For Still's Disease or antipyretic action in infants and children over 6 months to 14 years: 19.5mg/kg to 25mg/kg of body weight daily in divided doses three times daily.

Pediatric Use

Mefenamic acid is reported to be effective for pyrexia in pediatric patients over 6 months of age, and for pain in adolescents over 14 years of age.

Use in the Elderly

Impairment of renal function, sometimes leading to acute renal failure, has been reported. Elderly or debilitated patients seem unable to tolerate ulceration of bleeding as well as some other individuals; most spontaneous reports of fatal gastrointestinal events are in this patient population. (See Special Warnings and Special Precautions for Use – Gastrointestinal Effects)

CONTRAINDICATIONS

Because the potential exists for cross-sensitivity to aspirin or other nonsteroidal anti-inflammatory drugs, mefenamic acid should not be given to patients in whom these drugs induce symptoms of bronchospasm, allergic rhinitis, or urticaria.

Mefenamic acid is contraindicated in patients with active ulceration or chronic inflammation of either the upper or lower gastrointestinal tract and should be avoided in patients with pre-existing renal disease.

Mefenamic acid should not be used in patients with known hypersensitivity or any of the components of this drug.

Treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.

Patients with severe renal and hepatic failure.

Patients with severe heart failure.

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

The use of mefenamic acid with concomitant NSAIDs including COX-2 inhibitors should be avoided.

Cardiovascular Effects

NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocadial infarction, and stroke which can be fatal. This risk may increase with duration risk. Patients with known cardiovascular disease may be at greater risk. To minimize the potential risk for an adverse cardiovascular event in patients treated with mefenamic acid, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous cardiovascular symptoms. Patients should be informed about the signs and/or symptoms of serious cardiovascular toxicity and the steps to take if they occur (see Contraindications).

Hypertension

As with all NSAIDs, mefenamic acid can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cardiovascular events. NSAIDs, including mefenamic acid, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during initiation of therapy with mefenamic acid and throughout the course of therapy.

Fluid Retention and Edema

As with other drugs known to inhibit prostaglandin synthesis, fluid retention and edema have been observed in some patients taking NSAIDs, including mefenamic acid. Therefore, mefenamic acid should be used with caution in patients with compromised cardiac function and other conditions predisposing to, or worsened by, fluid retention. Patients with pre-existing congestive heart failure or hypertension should be closely monitored.

Gastrointestinal Effects

If diarrhea occurs, the dosage should be reduced or temporarily suspended. Symptoms may recur in certain patients following subsequent exposure. NSAIDs including mefenamic acid, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of stomach, small intestine, or large intestine, which can be fatal. When GI bleeding or ulceration occurs in patients receiving mefenamic acid, the treatment should be withdrawn. Patients most at risk of developing these types of GI complications with NSAIDs are the elderly, patients with cardiovascular disease, patients using concomitant aspirin, or patients with a prior history of, or active gastrointestinal disease, such as ulceration, GI bleeding or inflammatory conditions. Therefore, mefenamic acid should be used with caution in the patients (see Contraindications)

Skin Reaction

Serious skin reactions, some of them fatal including exfoliative dermatitis, Stevens Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs including mefenamic acid. Patients appear to be at highest risk for these events early in the course of therapy, the onset of the event occurring in the majority of cases within the first month of treatment. Mefenamic acid should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Laboratory Tests

A false-positive reaction for urinary bile, using the diazo tablet test, may result following mefenamic acid administration. If biliuria is suspected, other diagnostic procedures, such as the Harrison spot test, should be performed.

Renal Effects

In rare cases, NSAIDs, including mefenamic acid, may cause interstitial nephritis, glomerulitis, papillary necrosis and the nephrotic syndrome. NSAIDs inhibit the synthesis of renal prostaglandin which plays a supportive role in the maintenance of renal perfusion in patients whose renal blood flow and blood volume are decreased. In these patients, administration of an NSAID may precipitate overt renal decompensation, which is typically followed by recovery to pretreatment state upon discontinuation of NSAID therapy. Patients at greatest risk of such a reaction are those with congestive heart failure, liver cirrhosis, nephrotic syndrome, overt renal disease and the elderly. Such patients should be carefully monitored while receiving NSAID therapy.

Discontinuation of nonsteroidal anti-inflammatory drug (NSAID) therapy is typically followed by recovery to the pretreatment state. Since mefenamic acid metabolites are eliminated primarily by the kidneys, the drug should not be administered to patients with significantly impaired renal function.

Hematologic Effects

Mefenamic acid, like other nonsteroidal anti-inflammatory agents, can inhibit platelet aggregation and may prolong prothrombin time in patients on warfarin therapy. (see Interactions with other Medicinal Products and Other Forms of Interaction)

Hepatic effects

Borderline elevations of one or more liver function tests may occur in some patients receiving mefenamic acid therapy. These elevations may progress, may remain essentially unchanged, or may be transient with continued therapy. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with mefenamic acid. If abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systematic manifestations occur, mefenamic acid should be discontinued.

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Anticoagulants: Mefenamic acid has been shown to displace warfarin from protein binding sites, and may enhance the response to oral anticoagulants. Therefore, concurrent administration of mefenamic acid with oral anticoagulant drugs requires frequents prothrombin time monitoring.

Anti-hypertensives including diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonist (AII): NSAIDs can reduce the efficacy of diuretics and other antihypertensive drugs.

In patients with impaired renal function (e.g. dehydrated patients or elderly patients with compromised renal function), the co-administration of an ACE inhibitor or an AIIA with a cyclo-oxygenase inhibitor can increase the deterioration of the renal function, including the possibility of acute renal failure, which is usually reversible. The occurrence of these interactions should be considered in patients taking mefenamic acid with an ACE inhibitor or an AIIA.

Therefore, the concomitant administration of these drugs should be done with caution, especially in elderly patients. Patients should be adequately hydrated and the need to monitor the renal function should be assessed in the beginning of the concomitant treatment and periodically thereafter.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding.

Cyclosporine: Because of their effect on renal prostaglandins, cyclo-oxygenase inhibitors such as diclofenac can increase the risk of nephrotoxicity with cyclosporine.

Hypoglycemic agents: There have been reports of changes in the effects of oral hypoglycemic agents in the presence of NSAIDs. Therefore, mefenamic acid should be administered with caution in patients receiving insulin or oral hypoglycemic agents.

Lithium: Nonsteroidal anti-inflammatory drugs (NSAIDs), including mefenamic acid have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. Thus, when mefenamic acid and lithium are administered concurrently, patients should be observed carefully for signs of lithium toxicity.

Methotrexate: Caution is advised when methotrexate is administered concurrently with NSAIDs, including mefenamic acid, because NSAID administration may result in increased plasma levels of methotrexate.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

PREGNANCY AND LACTATION

Pregnancy

(see Preclinical Safety)

Since there are no adequate and well-controlled studies in pregnant women, this drug should be used only if the potential benefits to the mother justify the possible risk to the fetus. It is known if mefenamic acid or its metabolites cross the placenta. However, because of the effects of drugs in this class (i.e., inhibitors of prostaglandin synthesis) on the fetal cardiovascular system (e.g., premature closure of the ductus arteriosus), the use of mefenamic acid in pregnant women is not recommended. Mefenamic acid inhibits prostaglandin synthesis which may result in prolongation of pregnancy and interference with labor when administered late in the pregnancy. Women on mefenamic acid therapy should consult their physician if they decide to become pregnant.

Lactation

Trace amounts of mefenamic acid may be present in breast milk and transmitted to the nursing infant.

Therefore, mefenamic acid should not be taken by nursing mothers.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINE

The effects of mefenamic acid on the ability to drive or use machinery has not been systematically evaluated.

UNDESIRABLE EFFECTS

Blood and lymphatic system disorders: agranulocytosis, aplastic anemia, autoimmune hemolytic anemia, bone marrow hypoplasia, decreased hematocrit, eosinophilia, leukopenia, pancytopenia, and thrombocytopenic purpura.

Immune system disorders: anaphylaxis

Metabolism and nutrition disorder: glucose intolerance in diabetic patients, hyponatremia

Psychiatric disorders: nervousness

Nervous system disorders: aseptic meningitis, blurred vision, convulsions, dizziness, drowsiness, headache, and insomnia.

Eye disorders: eye irritation, reversible loss of color vision

Ear and labyrinth disorders: ear pain

Cardiac disorders: palpitation

Vascular disorders: hypotension

Respiratory, thoracic and mediastinal disorders: asthma, dyspnea

Gastrointestinal disorders:

The most frequently reported side effects associated with mefenamic acid involve the gastrointestinal tract. Diarrhea appears to be the most common side effect and is usually dose-related. It generally subsides on dosage reduction, and rapidly disappears on termination of therapy. Some patients may not be able to continue therapy.

The following are the most common gastrointestinal side effects: abdominal pain, diarrhea and nausea with or without vomiting.

Less frequently reported gastrointestinal/hepatobiliary side effects include: anorexia, cholestatic jaundice, colitis, constipation, enterocolitis, flatulence, gastric ulceration with and without hemorrhage, mild hepatic toxicity, hepatitis, hepatorenal syndrome, pyrosis, pancreatitis and steatorrhea.

Skin and subcutaneous tissue disorders: angioedema, edema of the larynx, erythema multiforme, facial edema, Lyell's syndrome (toxic epidermal necrolysis), perspiration, pruritus, rash, Stevens-Johnson syndrome and urticaria.

Renal and urinary disorders: dysuria, hematuria, renal failure including papillary necrosis.

OVERDOSE

Following accidental overdosage, the stomach should be emptied immediately by inducing emesis, or by gastric lavage, followed by administration of activated charcoal. Vital functions should be monitored and supported. Hemodialysis is of little value since mefenamic acid and its metabolites are firmly bound to plasma proteins.

Seizures, acute renal failure, and coma have been reported with mefenamic acid overdoses. Overdose has led to fatalities.

PHARMACODYNAMIC PROPERTIES

Mechanism of Action

Mefenamic acid is a nonsteroidal agent with demonstrated anti-inflammatory, analgesic, and antipyretic activity in laboratory animals. It is not a narcotic. Mefenamic acid was found to inhibit prostaglandin synthesis and to compete for binding at the prostaglandin receptor sites in animal models.

PHARMACOKINETICS PROPERTIES

Absorption

Mefenamic acid is rapidly absorbed from the gastrointestinal tract. Following administration of a one gram dose to adult, peak plasma levels of 10mcg/ml occur in 1 to 4 hours, with a half-life of 2 hours. Plasma levels are proportional to dose, following multiple doses, with no drug accumulation. One gram of mefenamic acid administered four times daily produces peak blood levels of 20mcg/ml by the second day of administration.

Distribution

Mefenamic acid is extensively bound to plasma proteins.

Metabolism

Mefenamic acid metabolism is predominantly mediated via cytochrome P450 CYP 2C9 in the liver. Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered mefenamic acid with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

Elimination

Following a single oral dose, 52-67% of the dose was recovered from the urine as unchanged drug or one of two metabolites. Assay of stools over 3 days accounted for 20-25% of the dose, chiefly as unconjugated metabolite II.

PRECLINICAL SAFETY

Rats given up to 10 times the human dose showed decreased fertility delay in parturition, and a decreased rate of survival to weaning. No fetal abnormalities were observed in this study and in another study in dogs receiving 10 times the human dose.

SPECIAL PRECAUTIONS FOR STORAGE

Store at temperature not exceeding 30^oC.