Glycopyrrolate 2 MG Oral Tablet

Generic Name: GLYCOPYRROLATE
Brand Name: Glycopyrrolate
  • Substance Name(s):
  • GLYCOPYRROLATE

WARNINGS

In the presence of a high environmental temperature, heat prostration (fever and heat stroke due to decreased sweating) can occur with use of glycopyrrolate.

Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomyor colostomy .

In this instance treatment with this drug would be inappropriate and possibly harmful.

Glycopyrrolate may produce drowsiness and blurred vision.

In this event, the patient should be warned not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery, or performing hazardous work while taking this drug.

Theoretically, with overdosage, a curare-like action may occur, i.e., neuro-muscular blockade leading to muscular weakness and possible paralysis.

Pregnancy The safety of this drug during pregnancy has not been established.

The use of any drug during pregnancy requires that potential benefits of the drug be weighed against possible hazards to mother and child.

Reproduction studies in rats revealed no teratogenic effects from glycopyrrolate; however, the potent anticholinergic action of this agent resulted in diminished rates of conception and of survival at weaning, in a dose-related manner.

Other studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate.

Information on possible adverse effects in the pregnant female is limited to uncontrolled data derived from marketing experience.

Such experience has revealed no reports of teratogenic or other fetus-damaging potential.

No controlled studies to establish the safety of the drug in pregnancy have been performed.

Nursing Mothers It is not known whether this drug is excreted in human milk.

As a general rule, nursing should not be undertaken while a patient is on a drug since many drugs are excreted in human milk.

Pediatric Use Since there is no adequate experience in pediatric patients who have received this drug, safety and efficacy in pediatric patients have not been established.

DRUG INTERACTIONS

There are no known drug interactions.

OVERDOSAGE

The symptoms of overdosage of glycopyrrolate are peripheral in nature rather than central.

To guard against further absorption of the drug-use gastric lavage, cathartics and/or enemas.

To combat peripheral anticholinergic effects (residual mydriasis, dry mouth, etc.)-utilize a quaternary ammonium anticholinesterase, such as neostigmine methylsulfate.

To combat hypotension-use pressor amines (norepinephrine, metaraminol) i.v.; and supportive care.

To combat respiratory depression-administer oxygen; utilize a respiratory stimulant such as Dopram®* i.v.; artificial respiration.

DESCRIPTION

Glycopyrrolate tablets contain the synthetic anticholinergic glycopyrrolate.

Glycopyrrolate is a quaternary ammonium compound with the following chemical name: 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide.

Its empirical formula is C 19 H 28 BrNO 3 , its molecular weight is 398.33, and its structural formula is: Each 1 mg tablet contains: Glycopyrrolate, USP 1mg Each 2 mg tablet contains: Glycopyrrolate, USP 2mg Inactive Ingredients: Dibasic Calcium Phosphate, Lactose, Magnesium Stearate, Povidone, Sodium Starch Glycolate this is the structure

HOW SUPPLIED

Glycopyrrolate tablets 1 mg are bisected, compressed white, round tablets debossed “K” above the bisect and “400” below the bisect on one side of the tablet, and plain on the other side.

Available in bottles of 100 (NDC 49884-065-01).

Glycopyrrolate tablets 2 mg are bisected, compressed white, round tablets debossed “K” above the bisect and “401” below the bisect on one side of the tablet, and plain on the other side.

Available in bottles of 100 (NDC 49884-066-01).

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Dispense in tight container.

Rx only * Dopram ® is a registered trademark of Baxter Healthcare Corporation.

Manufactured by: Par Pharmaceutical Companies, Inc.

Spring Valley, NY 10977 Rev: 07/2010 OS065-01-1-02

INDICATIONS AND USAGE

For use as adjunctive therapy in the treatment of peptic ulcer.

PEDIATRIC USE

Pediatric Use Since there is no adequate experience in pediatric patients who have received this drug, safety and efficacy in pediatric patients have not been established.

PREGNANCY

Pregnancy The safety of this drug during pregnancy has not been established.

The use of any drug during pregnancy requires that potential benefits of the drug be weighed against possible hazards to mother and child.

Reproduction studies in rats revealed no teratogenic effects from glycopyrrolate; however, the potent anticholinergic action of this agent resulted in diminished rates of conception and of survival at weaning, in a dose-related manner.

Other studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate.

Information on possible adverse effects in the pregnant female is limited to uncontrolled data derived from marketing experience.

Such experience has revealed no reports of teratogenic or other fetus-damaging potential.

No controlled studies to establish the safety of the drug in pregnancy have been performed.

NUSRING MOTHERS

Nursing Mothers It is not known whether this drug is excreted in human milk.

As a general rule, nursing should not be undertaken while a patient is on a drug since many drugs are excreted in human milk.

DOSAGE AND ADMINISTRATION

The dosage of glycopyrrolate should be adjusted to the needs of the individual patient to assure symptomatic control with a minimum of adverse reactions.

The presently recommended maximum daily dosage of glycopyrrolate is 8 mg.

Glycopyrrolate Tablets 1 mg.

The recommended initial dosage of glycopyrrolate for adults is one tablet three times daily (in the morning, early afternoon, and at bedtime).

Some patients may require two tablets at bedtime to assure overnight control of symptoms.

For maintenance, a dosage of one tablet twice a day is frequently adequate.

Glycopyrrolate Tablets 2 mg.

The recommended dosage of glycopyrrolate for adults is one tablet two or three times daily at equally spaced intervals.

Glycopyrrolate tablets are not recommended for use in pediatric patients under the age of 12 years.

Amitriptyline Hydrochloride 100 MG Oral Tablet

WARNINGS

Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.

The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.

There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.

The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications.

These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18–24 5 additional cases Decreases Compared to Placebo 25–64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials.

There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.

Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Prescriptions for amitriptyline hydrochloride tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.

Such monitoring should include daily observation by families and caregivers.

Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder.

It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.

Whether any of the symptoms described above represent such a conversion is unknown.

However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

It should be noted that amitriptyline hydrochloride tablets are not approved for use in treating bipolar depression.

Amitriptyline hydrochloride may block the antihypertensive action of guanethidine or similarly acting compounds.

It should be used with caution in patients with a history of seizures and, because of its atropine-like action, in patients with a history of urinary retention or angle-closure glaucoma.

In patients with angle-closure glaucoma, even average doses may precipitate an attack.

Patients with cardiovascular disorders should be watched closely.

Tricyclic antidepressant drugs, including amitriptyline hydrochloride, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia, and prolongation of the conduction time.

Myocardial infarction and stroke have been reported with drugs of this class.

Close supervision is required when amitriptyline hydrochloride is given to hyperthyroid patients or those receiving thyroid medication.

Amitriptyline hydrochloride may enhance the response to alcohol and the effects of barbiturates and other CNS depressants.

In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage.

Delirium has been reported with concurrent administration of amitriptyline and disulfiram.

The pupillary dilation that occurs following use of many antidepressant drugs, including amitriptyline hydrochloride tablets, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Angle-Closure Glaucoma: Usage in Pregnancy: Pregnancy Category C – Teratogenic effects were not observed in mice, rats, or rabbits when amitriptyline was given orally at doses of 2 to 40 mg/kg/day (up to 13 times the maximum recommended human dose*).

Studies in literature have shown amitriptyline to be teratogenic in mice and hamsters when given by various routes of administration at doses of 28 to 100 mg/kg/day (9 to 33 times the maximum recommended human dose), producing multiple malformations.

Another study in the rat reported that an oral dose of 25 mg/kg/day (8 times the maximum recommended human dose) produced delays in ossification of fetal vertebral bodies without other signs of embryotoxicity.

In rabbits, an oral dose of 60 mg/kg/day (20 times the maximum recommended human dose) was reported to cause incomplete ossification of the cranial bones.

Amitriptyline has been shown to cross the placenta.

Although a causal relationship has not been established, there have been a few reports of adverse events, including CNS effects, limb deformities, or developmental delay, in infants whose mothers had taken amitriptyline during pregnancy.

There are no adequate and well-controlled studies in pregnant women.

Amitriptyline hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Nursing Mothers: Amitriptyline is excreted into breast milk.

In one report in which a patient received amitriptyline 100 mg/day while nursing her infant, levels of 83 to 141 ng/mL were detected in the mother’s serum.

Levels of 135 to 151 ng/mL were found in the breast milk, but no trace of the drug could be detected in the infant’s serum.

Because of the potential for serious adverse reactions in nursing infants from amitriptyline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Usage in Pediatric Patients: In view of the lack of experience with the use of this drug in pediatric patients, it is not recommended at the present time for patients under 12 years of age.

DRUG INTERACTIONS

Drug Interactions: Topiramate – Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient’s clinical response and not on the basis of plasma levels.

Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7 to 10% of Caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available.

Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses.

Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA).

In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers.

An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy.

The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide).

While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition.

The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved.

Nevertheless, caution is indicated in the coadministration of TCAs with any of SSRIs and also in switching from one class to the other.

Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug.

Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required.

It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6.

Monoamine oxidase inhibitors – see section.

Guanethidine or similarly acting compounds; thyroid medication; alcohol, barbiturates and other CNS depressants; and disulfiram – see section.

CONTRAINDICATIONS WARNINGS When amitriptyline hydrochloride is given with anticholinergic agents or sympathomimetic drugs, including epinephrine combined with local anesthetics, close supervision and careful adjustment of dosages are required.

Hyperpyrexia has been reported when amitriptyline hydrochloride is administered with anticholinergic agents or with neuroleptic drugs, particularly during hot weather.

Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type drugs.

Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants, thereby delaying elimination and increasing steady-state concentrations of these drugs.

Clinically significant effects have been reported with the tricyclic antidepressants when used concomitantly with cimetidine.

Increases in plasma levels of tricyclic antidepressants, and in the frequency and severity of side effects, particularly anticholinergic, have been reported when cimetidine was added to the drug regimen.

Discontinuation of cimetidine in well-controlled patients receiving tricyclic antidepressants and cimetidine may decrease the plasma levels and efficacy of the antidepressants.

Caution is advised if patients receive large doses of ethchlorvynol concurrently.

Transient delirium has been reported in patients who were treated with one gram of ethchlorvynol and 75 to 150 mg of amitriptyline hydrochloride.

OVERDOSAGE

Deaths may occur from overdosage with this class of drugs.

Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose.

As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment.

Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible.

Manifestations: Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma.

Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity.

In addition, a rightward axis shift in the terminal QRS complex together with a prolonged QT interval and sinus tachycardia are specific and sensitive indicators of first generation tricyclic overdose.

The absence of these findings is not exclusionary.

Prolonged PR interval, ST-T wave changes, ventricular tachycardia and fibrillation may also occur.

Other signs of overdose may include: impaired myocardial contractility, confusion, disturbed concentration, transient visual hallucinations, dilated pupils, disorders of ocular motility, agitation, hyperactive reflexes, polyradiculoneuropathy, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under .

ADVERSE REACTIONS Management: General – Obtain an ECG and immediately initiate cardiac monitoring.

Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination.

A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary.

If signs of toxicity occur at any time during the period, extended monitoring is required.

There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination.

Monitoring of plasma drug levels should not guide management of the patient.

Gastrointestinal Decontamination: All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination.

This should include large volume gastric lavage followed by activated charcoal.

If consciousness is impaired, the airway should be secured prior to lavage.

EMESIS IS CONTRAINDICATED.

Cardiovascular: A maximal limb-lead QRS duration of ≥0.10 seconds may be the best indication of the severity of the overdose.

Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55.

If the pH response is inadequate, hyperventilation may also be used.

Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring.

A pH > 7.60 or a pCO < 20 mm Hg is undesirable.

Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin.

Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).

2 In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with the acute toxicity.

However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning.

CNS: In patients with CNS depression early intubation is advised because of the potential for abrupt deterioration.

Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin).

Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.

Psychiatric Follow-up: Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase.

Psychiatric referral may be appropriate.

Pediatric Management: The principles of management of pediatric and adult overdosages are similar.

It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

DESCRIPTION

Amitriptyline HCl is 3-(10,11-dihydro-5H-dibenzo [a, ] cycloheptene-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride.

Its empirical formula is C H N•HCl, and its structural formula is: d 20 23 Amitriptyline HCl, a dibenzocycloheptadiene derivative, has a molecular weight of 313.87.

It is a white, odorless, crystalline compound which is freely soluble in water.

Amitriptyline HCl is supplied as 10 mg, 25 mg, 50 mg, 75 mg, 100 mg or 150 mg tablets.

Each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate, sodium starch glycolate and titanium dioxide.

The 10 mg tablets also contain FD&C blue #1 lake.

The 25 mg tablets also contain D&C yellow #10 lake and FD&C blue #2 lake.

The 50 mg tablets also contain synthetic black iron oxide, synthetic red iron oxide and synthetic yellow iron oxide.

The 75 mg tablets also contain FD&C yellow #6 lake.

The 100 mg tablets also contain D&C red #33 lake and FD&C red #40 lake.

The 150 mg tablets also contain FD&C blue #2 lake and FD&C yellow #6 lake.

This is an image of the sturctural formula of Amitriptyline HCl.

HOW SUPPLIED

NDC:54569-0172-0 in a BOTTLE, PLASTIC of 30 TABLET, FILM COATEDS NDC:54569-0172-1 in a BOTTLE, PLASTIC of 100 TABLET, FILM COATEDS NDC:54569-0172-4 in a BOTTLE, PLASTIC of 14 TABLET, FILM COATEDS NDC:54569-0172-6 in a BOTTLE, PLASTIC of 90 TABLET, FILM COATEDS NDC:54569-0172-8 in a BOTTLE, PLASTIC of 120 TABLET, FILM COATEDS

GERIATRIC USE

Geriatric Use: Clinical experience has not identified differences in responses between elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic function, concomitant disease and other drug therapy in elderly patients.

Geriatric patients are particularly sensitive to the anticholinergic side effects of tricyclic antidepressants including amitriptyline hydrochloride.

Peripheral anticholinergic effects include tachycardia, urinary retention, constipation, dry mouth, blurred vision, and exacerbation of narrow-angle glaucoma.

Central nervous system anticholinergic effects include cognitive impairment, psychomotor slowing, confusion, sedation, and delirium.

Elderly patients taking amitriptyline hydrochloride may be at increased risk for falls.

Elderly patients should be started on low doses of amitriptyline hydrochloride and observed closely (see ).

DOSAGE AND ADMINISTRATION

INDICATIONS AND USAGE

For the relief of symptoms of depression.

Endogenous depression is more likely to be alleviated than are other depressive states.

PEDIATRIC USE

Usage in Pediatric Patients: In view of the lack of experience with the use of this drug in pediatric patients, it is not recommended at the present time for patients under 12 years of age.

PREGNANCY

Usage in Pregnancy: Pregnancy Category C – Teratogenic effects were not observed in mice, rats, or rabbits when amitriptyline was given orally at doses of 2 to 40 mg/kg/day (up to 13 times the maximum recommended human dose*).

Studies in literature have shown amitriptyline to be teratogenic in mice and hamsters when given by various routes of administration at doses of 28 to 100 mg/kg/day (9 to 33 times the maximum recommended human dose), producing multiple malformations.

Another study in the rat reported that an oral dose of 25 mg/kg/day (8 times the maximum recommended human dose) produced delays in ossification of fetal vertebral bodies without other signs of embryotoxicity.

In rabbits, an oral dose of 60 mg/kg/day (20 times the maximum recommended human dose) was reported to cause incomplete ossification of the cranial bones.

Amitriptyline has been shown to cross the placenta.

Although a causal relationship has not been established, there have been a few reports of adverse events, including CNS effects, limb deformities, or developmental delay, in infants whose mothers had taken amitriptyline during pregnancy.

There are no adequate and well-controlled studies in pregnant women.

Amitriptyline hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers: Amitriptyline is excreted into breast milk.

In one report in which a patient received amitriptyline 100 mg/day while nursing her infant, levels of 83 to 141 ng/mL were detected in the mother’s serum.

Levels of 135 to 151 ng/mL were found in the breast milk, but no trace of the drug could be detected in the infant’s serum.

Because of the potential for serious adverse reactions in nursing infants from amitriptyline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

BOXED WARNING

Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.

Anyone considering the use of amitriptyline hydrochloride tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older.

Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide.

Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised of the need for close observation and communication with the prescriber.

Amitriptyline hydrochloride tablets are not approved for use in pediatric patients (see , , and .) Warnings: Clinical Worsening and Suicide Risk Precautions: Information for Patients Precautions: Pediatric Use

INFORMATION FOR PATIENTS

Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with amitriptyline hydrochloride tablets and should counsel them in its appropriate use.

A patient about is available for amitriptyline hydrochloride tablets.

The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents.

Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

The complete text of the Medication Guide is reprinted at the end of this document.

Medication Guide “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking amitriptyline hydrochloride tablets.

While on therapy with amitriptyline hydrochloride, patients should be advised as to the possible impairment of mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle.

Patients should be advised that taking amitriptyline hydrochloride tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma.

Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy.

Open-angle glaucoma is not a risk factor for angle-closure glaucoma.

Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

DOSAGE AND ADMINISTRATION

Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance.

Initial Dosage for Adults: For outpatients 75 mg of amitriptyline HCl a day in divided doses is usually satisfactory.

If necessary, this may be increased to a total of 150 mg per day.

Increases are made preferably in the late afternoon and/or bedtime doses.

A sedative effect may be apparent before the antidepressant effect is noted, but an adequate therapeutic effect may take as long as 30 days to develop.

An alternate method of initiating therapy in outpatients is to begin with 50 to 100 mg amitriptyline HCl at bedtime.

This may be increased by 25 or 50 mg as necessary in the bedtime dose to a total of 150 mg per day.

Hospitalized patients may require 100 mg a day initially.

This can be increased gradually to 200 mg a day if necessary.

A small number of hospitalized patients may need as much as 300 mg a day.

Adolescent and Elderly Patients: In general, lower dosages are recommended for these patients.

Ten mg 3 times a day with 20 mg at bedtime may be satisfactory in adolescent and elderly patients who do not tolerate higher dosages.

Maintenance: The usual maintenance dosage of amitriptyline HCl is 50 to 100 mg per day.

In some patients 40 mg per day is sufficient.

For maintenance therapy the total daily dosage may be given in a single dose preferably at bedtime.

When satisfactory improvement has been reached, dosage should be reduced to the lowest amount that will maintain relief of symptoms.

It is appropriate to continue maintenance therapy 3 months or longer to lessen the possibility of relapse.

Usage in Pediatric Patients In view of the lack of experience with the use of this drug in pediatric patients, it is not recommended at the present time for patients under 12 years of age.

Plasma Levels Because of the wide variation in the absorption and distribution of tricyclic antidepressants in body fluids, it is difficult to directly correlate plasma levels and therapeutic effect.

However, determination of plasma levels may be useful in identifying patients who appear to have toxic effects and may have excessively high levels, or those in whom lack of absorption or noncompliance is suspected.

Because of increased intestinal transit time and decreased hepatic metabolism in elderly patients, plasma levels are generally higher for a given oral dose of amitriptyline hydrochloride than in younger patients.

Elderly patients should be monitored carefully and quantitative serum levels obtained as clinically appropriate.

Adjustment in dosage should be made according to the patient’s clinical response and not on the basis of plasma levels.**

guaifenesin 300 MG per 15 ML Oral Solution

WARNINGS

Warnings Do not exceed recommended dosage

INDICATIONS AND USAGE

Uses Help loosen phlegm (mucus) and thin bronchial secretions to drain bronchial tubes and make cough more productive.

INACTIVE INGREDIENTS

Inactive ingredients Blue cohosh, citric acid, echinacea, eucalyptus oil, ginkgo biloba, glycerin, gold seal root, honey flavor, horehound herb, licorice root, menthol, mullein, myrrh, potassium sorbate, slippery elm bark, sodium benzoate, propylene glycol, water, sodium chloride, sucralose, wild cherry bark and zinc sulfate.

PURPOSE

Purpose Expectorant

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

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

DOSAGE AND ADMINISTRATION

Directions Do not take more than 6 doses in any 24-hour period Shake well before use Age Dose Adults and children 12 years and over 10 mL (2 tsps) every 4 hours Children 6 to under 12 years of age.

5 mL (1 tsps) every 4 hours Children under 6 years of age Do not use

PREGNANCY AND BREAST FEEDING

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

DO NOT USE

Do not use if you have a chronic pulmonary disease or shortness of breath unless directed by a doctor Ask the doctor before use if you have cough that occurs with too much phlegm (mucus) cough that lasts or is chronic such as occurs with smoking, asthma, chronic bronchitis or emphysema

STOP USE

Stop use and ask the doctor if Nervoisness, dizziness or sleeplessness occurs.

Cough persists for more than 1 week, tends to recur, or accompanied by fever, rash or persistent headache.

A persistent cough may be sign of a serious condition

ACTIVE INGREDIENTS

Acvtive ingredients: (in each 5ml) Purpose Guaifenesin 100 mg ……………………………..

Expectorant

HYDROcodone bitartrate 2.5 MG / acetaminophen 500 MG Oral Tablet

WARNINGS

Respiratory Depression: At high doses or in sensitive patients, hydrocodone may produce dose-related respiratory depression by acting directly on the brain stem respiratory center.

Hydrocodone also affects the center that controls respiratory rhythm, and may produce irregular and periodic breathing.

Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a preexisting increase in intracranial pressure.

Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries.

Acute Abdominal Conditions: The administration of narcotics may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Misuse, Abuse, and Diversion of Opioids: Hydrocodone bitartrate and acetaminophen tablets contain hydrocodone, an opioid agonist, and is a Schedule III controlled substance.

Opioid agonists have the potential for being abused and are sought by abusers and people with addiction disorders, and are subject to diversion.

Hydrocodone bitartrate and acetaminophen tablets can be abused in a manner similar to other opioid agonists, legal or illicit.

This should be considered when prescribing or dispensing hydrocodone bitartrate and acetaminophen tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion (see DRUG ABUSE AND DEPENDENCE ).

DRUG INTERACTIONS

Drug Interactions: Patients receiving other narcotic analgesics, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants (including alcohol) concomitantly with hydrocodone bitartrate and acetaminophen tablets may exhibit an additive CNS depression.

When combined therapy is contemplated, the dose of one or both agents should be reduced.

The use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone.

OVERDOSAGE

Following an acute overdosage, toxicity may result from hydrocodone or acetaminophen.

Signs and Symptoms: Hydrocodone: Serious overdose with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension.

In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur.

Acetaminophen: In acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect.

Renal tubular necrosis, hypoglycemic coma, and thrombocytopenia may also occur.

Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise.

Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.

In adults, hepatic toxicity has rarely been reported with acute overdoses of less than 10 grams, or fatalities with less than 15 grams.

Treatment: A single or multiple overdose with hydrocodone and acetaminophen is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended.

Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption.

Vomiting should be induced mechanically, or with syrup of ipecac, if the patient is alert (adequate pharyngeal and laryngeal reflexes).

Oral activated charcoal (1 g/kg) should follow gastric emptying.

The first dose should be accompanied by an appropriate cathartic.

If repeated doses are used, the cathartic might be included with alternate doses as required.

Hypotension is usually hypovolemic and should respond to fluids.

Vasopressors and other supportive measures should be employed as indicated.

A cuffed endotracheal tube should be inserted before gastric lavage of the unconscious patient and, when necessary, to provide assisted respiration.

Meticulous attention should be given to maintaining adequate pulmonary ventilation.

In severe cases of intoxication, peritoneal dialysis, or preferably hemodialysis may be considered.

If hypoprothrombinemia occurs due to acetaminophen overdose, vitamin K should be administered intravenously.

Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with opioid overdose.

Naloxone hydrochloride 0.4 mg to 2 mg is given parenterally.

Since the duration of action of hydrocodone may exceed that of the naloxone, the patient should be kept under continuous surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration.

A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression.

If the dose of acetaminophen may have exceeded 140 mg/kg, acetylcysteine should be administered as early as possible.

Serum acetaminophen levels should be obtained, since levels four or more hours following ingestion help predict acetaminophen toxicity.

Do not await acetaminophen assay results before initiating treatment.

Hepatic enzymes should be obtained initially, and repeated at 24-hour intervals.

Methemoglobinemia over 30% should be treated with methylene blue by slow intravenous administration.

The toxic dose for acetaminophen for adults is 10 g.

DESCRIPTION

Hydrocodone bitartrate and acetaminophen is supplied in tablet form for oral administration.

Hydrocodone bitartrate is an opioid analgesic and antitussive and occurs as fine, white crystals or as a crystalline powder.

It is affected by light.

The chemical name is 4,5α-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5).

It has the following structural formula: Acetaminophen, 4′-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic.

It has the following structural formula: Hydrocodone Bitartrate and Acetaminophen Tablets, USP 2.5 mg/500 mg Each tablet contains: Hydrocodone Bitartrate ………….

2.5 mg Acetaminophen …………………….

500 mg In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, crospovidone, FD&C Red #3, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized corn starch, stearic acid, and sucrose.

Meets USP Dissolution Test 1.

Hydrocodone Bitartrate and Acetaminophen Tablets, USP 5 mg/325 mg Each tablet contains: Hydrocodone Bitartrate ……………..

5 mg Acetaminophen ………………………..

325 mg In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, sodium lauryl sulfate, stearic acid and sugar spheres which are composed of starch derived from corn, FD&C Red #40, FD&C Yellow #6, and sucrose.

Meets USP Dissolution Test 2.

Hydrocodone Bitartrate and Acetaminophen Tablets, USP 5 mg/500 mg Each tablet contains: Hydrocodone Bitartrate ………….

5 mg Acetaminophen …………………….

500 mg In addition each tablet contains the following inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, and sodium starch glycolate.

Meets USP Dissolution Test 1.

Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/325 mg Each tablet contains: Hydrocodone Bitartrate ………….

7.5 mg Acetaminophen …………………….

325 mg In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, FD&C Red #40 aluminum lake, FD&C Yellow #6 aluminum lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, sodium lauryl sulfate, stearic acid.

Meets USP Dissolution Test 2.

Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/500 mg Each tablet contains: Hydrocodone Bitartrate ………….

7.5 mg Acetaminophen …………………….

500 mg In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, crospovidone, FD&C Blue #1, FD&C Yellow #5, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized corn starch, stearic acid, and sucrose.

Meets USP Dissolution Test 1.

Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/650 mg Each tablet contains: Hydrocodone Bitartrate ………….

7.5 mg Acetaminophen …………………….

650 mg In addition each tablet contains the following inactive ingredients: croscarmellose sodium, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized corn starch, and stearic acid.

Meets USP Dissolution Test 1.

Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/750 mg Each tablet contains: Hydrocodone Bitartrate ………….

7.5 mg Acetaminophen …………………….

750 mg In addition each tablet contains the following inactive ingredients: croscarmellose sodium, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized corn starch, and stearic acid.

Meets USP Dissolution Test 1.

Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/325 mg Each tablet contains: Hydrocodone Bitartrate …………

10 mg Acetaminophen …………………….

325 mg In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, crospovidone, D&C Yellow #10 lake, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized corn starch, and stearic acid.

Meets USP Dissolution Test 1.

Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/500 mg Each tablet contains: Hydrocodone Bitartrate …………

10 mg Acetaminophen …………………….

500 mg In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, crospovidone, D&C Red #27 aluminum lake, D&C Red #30 aluminum lake, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized corn starch, and stearic acid.

Meets USP Dissolution Test 1.

Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/650 mg Each tablet contains: Hydrocodone Bitartrate …………

10 mg Acetaminophen …………………….

650 mg In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, crospovidone, FD&C Blue #1 aluminum lake, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized corn starch, and stearic acid.

Meets USP Dissolution Test 1.

Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/660 mg Each tablet contains: Hydrocodone Bitartrate …………

10 mg Acetaminophen …………………….

660 mg In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized corn starch, and stearic acid.

Meets USP Dissolution Test 1.

This is an image of the structural formula of Hydrocodone bitartrate.

This is an image of the structural formula of Acetaminophen.

HOW SUPPLIED

Hydrocodone Bitartrate and Acetaminophen Tablets, USP 2.5 mg/500 mg are supplied as white with bright pink specks, capsule-shaped, scored tablets, debossed “3591” on one side and debossed “V” on the reverse side.

The tablets are supplied in containers of: 8 NDC 21695-579-08 16 NDC 21695-579-16 28 NDC 21695-579-28 30 NDC 21695-579-30 60 NDC 21695-579-60 Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure.

A Schedule CIII Narcotic.

GERIATRIC USE

Geriatric Use: Clinical studies of hydrocodone bitartrate and acetaminophen tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hydrocodone and the major metabolites of acetaminophen are known to be substantially excreted by the kidney.

Thus the risk of toxic reactions may be greater in patients with impaired renal function due to the accumulation of the parent compound and/or metabolites in the plasma.

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.

Hydrocodone may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of hydrocodone bitartrate and acetaminophen tablets and observed closely.

INDICATIONS AND USAGE

Hydrocodone bitartrate and acetaminophen tablets are indicated for the relief of moderate to moderately severe pain.

PEDIATRIC USE

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

PREGNANCY

Pregnancy: Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women.

Hydrocodone bitartrate and acetaminophen tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent.

The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever.

The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose.

There is no consensus on the best method of managing withdrawal.

NUSRING MOTHERS

Nursing Mothers: Acetaminophen is excreted in breast milk in small amounts, but the significance of its effects on nursing infants is not known.

It is not known whether hydrocodone is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from hydrocodone and acetaminophen, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

INFORMATION FOR PATIENTS

Information for Patients: Hydrocodone, like all narcotics, may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery; patients should be cautioned accordingly.

Alcohol and other CNS depressants may produce an additive CNS depression, when taken with this combination product, and should be avoided.

Hydrocodone may be habit-forming.

Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.

DOSAGE AND ADMINISTRATION

Dosage should be adjusted according to the severity of the pain and the response of the patient.

However, it should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related.

Hydrocodone Bitartrate and Acetaminophen Tablets, USP 2.5 mg/500 mg The usual adult dosage is one or two tablets every four to six hours as needed for pain.

The total daily dosage should not exceed 8 tablets.

Plasma-Lyte R Multiple Electrolytes Injectable Solution

WARNINGS

PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention.

PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present.

PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great care in patients with metabolic or respiratory alkalosis.

The administration of lactate or acetate ions should be done with great care in those conditions in which there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.

PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should not be administered simultaneously with blood through the same administration set because of the likelihood of coagulation.

The intravenous administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema.

The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection.

The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the injection.

In patients with diminished renal function, administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) may result in sodium or potassium retention.

PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is not for use in the treatment of lactic acidosis.

DESCRIPTION

PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration.

Each 100 mL contains 640 mg of Sodium Acetate Trihydrate, USP (C 2 H 3 NaO 2 •3H 2 O); 496 mg of Sodium Chloride, USP (NaCl); 89.6 mg of Sodium Lactate (C 3 H 5 NaO 3 ); 74.6 mg of Potassium Chloride, USP (KCl); 36.8 mg of Calcium Chloride, USP (CaCl 2 •2H 2 O); and 30.5 mg of Magnesium Chloride, USP (MgCl 2 •6H 2 O).

It contains no antimicrobial agents.

The pH is adjusted with hydrochloric acid.

The pH is 5.5 (4.0 to 8.0).

PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) administered intravenously has value as a source of water, electrolytes, and calories.

One liter has an ionic concentration of 140 mEq sodium, 10 mEq potassium, 5 mEq calcium, 3 mEq magnesium, 103 mEq chloride, 47 mEq acetate, and 8 mEq lactate.

The osmolarity is 312 mOsmol/L (calc).

Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.

Administration of substantially hypertonic solutions may cause vein damage.

The caloric content is 11 kcal/L.

The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic).

The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly.

Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million.

However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

HOW SUPPLIED

PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) in VIAFLEX plastic containers is available as shown below: Code Size (mL) NDC 2B2504 1000 NDC 0338-0177-04 Exposure of pharmaceutical products to heat should be minimized.

Avoid excessive heat.

It is recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product.

GERIATRIC USE

Geriatric Use Clinical studies of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.

Do not administer unless solution is clear and seal is intact.

INDICATIONS AND USAGE

PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is indicated as a source of water and electrolytes or as an alkalinizing agent.

PEDIATRIC USE

Pediatric Use Safety and effectiveness of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) in pediatric patients have not been established by adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population is referenced in the medical literature.

The warnings, precautions and adverse reactions identified in the label copy should be observed in the pediatric population.

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP).

It is also not known whether PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be given to a pregnant woman only if clearly needed.

DOSAGE AND ADMINISTRATION

As directed by a physician.

Dosage is dependent upon the age, weight and clinical condition of the patient as well as laboratory determinations.

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

All injections in VIAFLEX plastic containers are intended for intravenous administration using sterile equipment.

Additives may be incompatible.

Complete information is not available.

Those additives known to be incompatible should not be used.

Consult with pharmacist, if available.

If, in the informed judgment of the physician, it is deemed advisable to introduce additives, use aseptic technique.

Mix thoroughly when additives have been introduced.

Do not store solutions containing additives.

Estradiol 0.5 MG / norethindrone acetate 0.1 MG Oral Tablet

DRUG INTERACTIONS

7 Coadministration of estradiol with norethindrone acetate did not elicit any apparent influence on the pharmacokinetics of norethindrone acetate.

Similarly, no relevant interaction of norethindrone acetate on the pharmacokinetics of estradiol was found within the NETA dose range investigated in a single dose study.

Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism ( 7.1 ) 7.1 Metabolic Interactions Estradiol In-vitro and in-vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4).

Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism.

Inducers of CYP3A4 such as St.

John’s wort ( Hypericumperforatum ) preparations, phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile.

Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and result in side effects.

Norethindrone Acetate Drugs or herbal products that induce or inhibit cytochrome P-450 enzymes, including CYP3A4, may decrease or increase the serum concentrations of norethindrone.

OVERDOSAGE

10 Overdosage of estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women.

Treatment of overdose consists of discontinuation of Activella therapy with institution of appropriate symptomatic care.

DESCRIPTION

11 Activella 1 mg/0.5 mg is a single tablet for oral administration containing 1 mg of estradiol and 0.5 mg of norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), copovidone, talc, magnesium stearate, hypromellose and triacetin.

Activella 0.5 mg/0.1 mg is a single tablet for oral administration containing 0.5 mg of estradiol and 0.1 mg of norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), hydroxypropylcellulose, talc, magnesium stearate, hypromellose and triacetin.

Estradiol (E 2 ), an estrogen, is a white or almost white crystalline powder.

Its chemical name is estra-1, 3, 5 (10)-triene-3, 17β-diol hemihydrate with the empirical formula of C 18 H 24 O 2, ½ H 2 O and a molecular weight of 281.4.

The structural formula of E 2 is as follows: Estradiol Norethindrone acetate (NETA), a progestin, is a white or yellowish-white crystalline powder.

Its chemical name is 17β -acetoxy-19-nor-17α -pregn-4-en-20-yn-3-one with the empirical formula of C 22 H 28 O 3 and molecular weight of 340.5.

The structural formula of NETA is as follows: Norethindrone Acetate Estradiol Norethindrone Acetate

CLINICAL STUDIES

14 14.1 Effects on Vasomotor Symptoms In a 12-week randomized clinical trial involving 92 subjects, Activella 1 mg/0.5 mg was compared to 1 mg of estradiol and to placebo.

The mean number and intensity of hot flushes were significantly reduced from baseline to week 4 and 12 in both the Activella 1 mg/0.5 mg and the 1 mg estradiol group compared to placebo (see Figure 2).

Figure 2 Mean Weekly Number of Moderate and Severe Hot Flushes in a 12-Week Study In a study conducted in Europe a total of 577 postmenopausal women were randomly assigned to either Activella 0.5 mg/0.1 mg, 0.5 mg E 2 /0.25 mg NETA, or placebo for 24 weeks of treatment.

The mean number and severity of hot flushes were significantly reduced at week 4 and week 12 in the Activella 0.5 mg/0.1 mg (see Figure 3) and 0.5 mg E 2 /0.25 mg NETA groups compared to placebo.

Figure 3 Mean Number of Moderate to Severe Hot Flushes for Weeks 0 Through 12 Figure 2 Figure 3 14.2 Effects on the Endometrium Activella 1 mg/0.5 mg reduced the incidence of estrogen-induced endometrial hyperplasia at 1 year in a randomized, controlled clinical trial.

This trial enrolled 1,176 subjects who were randomized to one of 4 arms: 1 mg estradiol unopposed (n=296), 1 mg E 2 + 0.1 mg NETA (n=294), 1 mg E 2 + 0.25 mg NETA (n=291), and Activella 1 mg/0.5 mg (n=295).

At the end of the study, endometrial biopsy results were available for 988 subjects.

The results of the 1 mg estradiol unopposed arm compared to Activella 1 mg/0.5 mg are shown in Table 4.

TABLE 4 INCIDENCE OF ENDOMETRIAL HYPERPLASIA WITH UNOPPOSED ESTRADIOL AND ACTIVELLA 1 MG/0.5 MG IN A 12-MONTH STUDY 1 mg E 2 (n=296) Activella 1 mg E 2 /0.5 mg NETA (n=295) 1 mg E 2 /0.25 mg NETA (n=291 ) 1 mg E 2 /0.1 mg NETA (n=294 ) No.

of subjects with histological evaluation at the end of the study 247 241 251 249 No.

(%) of subjects with endometrial hyperplasia at the end of the study 36 (14.6%) 1 (0.4%) 1 (0.4%) 2 (0.8%) 14.3 Effects on Uterine Bleeding or Spotting During the initial months of therapy, irregular bleeding or spotting occurred with Activella 1 mg/0.5 mg treatment.

However, bleeding tended to decrease over time, and after 12 months of treatment with Activella 1 mg/0.5 mg, about 86 percent of women were amenorrheic (see Figure 4).

Figure 4 Patients Treated with Activella 1 mg/0.5 mg with Cumulative Amenorrhea over Time Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 13 Intent to Treat Population, LOCF Note: the percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown.

If data were missing, the bleeding value from the last reported day was carried forward (LOCF).

In the clinical trial with Activella 0.5 mg/0.1 mg, 88 percent of women were amenorrheic after 6 months of treatment (See Figure 5).

Figure 5 Figure 4 Figure 5 14.4 Effects on Bone Mineral Density The results of two randomized, multicenter, calcium-supplemented (500-1000 mg per day), placebo-controlled, 2 year clinical trials have shown that Activella 1 mg/0.5 mg and estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women.

A total of 462 postmenopausal women with intact uteri and baseline BMD values for lumbar spine within 2 standard deviations of the mean in healthy young women (T-score > -2.0) were enrolled.

In a US trial, 327 postmenopausal women (mean time from menopause 2.5 to 3.1 years) with a mean age of 53 years were randomized to 7 groups (0.25 mg, 0.5 mg, and 1 mg of estradiol alone, 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and 2 mg estradiol with 1 mg norethindrone acetate, and placebo.) In a European trial (EU trial), 135 postmenopausal women (mean time from menopause 8.4 to 9.3 years) with a mean age of 58 years were randomized to 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and placebo.

Approximately 58 percent and 67 percent of the randomized subjects in the two clinical trials, respectively, completed the two clinical trials.

BMD was measured using dual-energy x-ray absorptiometry (DXA).

A summary of the results comparing Activella 1 mg/0.5 mg and estradiol 0.5 mg to placebo from the two prevention trials is shown in Table 5.

TABLE 5 PERCENTAGE CHANGE (MEAN ± SD) IN BONE MINERAL DENSITY (BMD) FOR ACTIVELLA 1 MG/0.5 MG AND 0.5 MG E 2 While Activella 0.5 mg/0.1 mg was not directly studied in these trials, the US trial showed that addition of NETA to estradiol enhances the effect on BMD; therefore the BMD changes expected from treatment with Activella 0.5 mg/0.1 mg should be at least as great as observed with estradiol 0.5 mg.

(Intent to Treat Analysis, Last Observation Carried Forward) US Trial EU Trial Placebo (n=37) 0.5 mg E 2 (n=31) Activella 1 mg/0.5 mg (n=37) Placebo (n=40) Activella 1 mg/0.5 mg (n=38) Lumbar spine -2.1 ± 2.9 2.3 ± 2.8 Significantly (p<0.001) different from placebo 3.8 ± 3.0 -0.9 ± 4.0 5.4 ± 4.8 Femoral neck -2.3 ± 3.4 0.3 ± 2.9 Significantly (p<0.007) different from placebo 1.8 ± 4.1 -1.0 ± 4.6 0.7 ± 6.1 Femoral trochanter -2.0 ± 4.3 1.7 ± 4.1 Significantly (p<0.002) different from placebo 3.7 ± 4.3 0.8 ± 6.9 6.3 ± 7.6 US = United States, EU = European The overall difference in mean percentage change in BMD at the lumbar spine in the US trial (1000 mg per day calcium) between Activella 1 mg/0.5 mg and placebo was 5.9 percent and between estradiol 0.5 mg and placebo was 4.4 percent.

In the European trial (500 mg per day calcium), the overall difference in mean percentage change in BMD at the lumbar spine was 6.3 percent.

Activella 1 mg/0.5 mg and estradiol 0.5 mg also increased BMD at the femoral neck and femoral trochanter compared to placebo.

The increase in lumbar spine BMD in the US and European clinical trials for Activella 1 mg/0.5 mg and estradiol 0.5 mg is displayed in Figure 6.

Figure 6 Percentage Change in Bone Mineral Density (BMD) ± SEM of the Lumbar Spine (L1-L4) for Activella 1 mg/0.5 mg and Estradiol 0.5 mg (Intent to Treat Analysis with Last Observation Carried Forward) Figure 6 14.5 Women’s Health Initiative Studies The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases.

The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome.

A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause.

These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.

WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early.

According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.

For those outcomes included in the WHI “global index,” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 6.

These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Table 6: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years Adapted from numerous WHI publications.

WHI publications can be viewed at www.nhlbi.nih.gov/whi.

, Results are based on centrally adjudicated data.

Event Relative Risk CE/MPA versus Placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-Years CHD events 1.23 (0.99-1.53) 41 34 Non-fatal MI 1.28 (1.00-1.63) 31 25 CHD death 1.10 (0.70-1.75) 8 8 All strokes 1.31 (1.03–1.68) 33 25 Ischemic stroke 1.44 (1.09–1.90) 26 18 Deep vein thrombosis Not included in “global index”.

1.95 (1.43–2.67) 26 13 Pulmonary embolism 2.13 (1.45–3.11) 18 8 Invasive breast cancer Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.

1.24 (1.01–1.54) 41 33 Colorectal cancer 0.61 (0.42–0.87) 10 16 Endometrial cancer 0.81 (0.48–1.36) 6 7 Cervical cancer 1.44 (0.47–4.42) 2 1 Hip fracture 0.67 (0.47–0.96) 11 16 Vertebral fractures 0.65 (0.46–0.92) 11 17 Lower arm/wrist fractures 0.71 (0.59–0.85) 44 62 Total fractures 0.76 (0.69–0.83) 152 199 Overall Mortality All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.

1.00 (0.83-1.19) 52 52 Global Index A subset of the events was combined in a “global index” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.

1.13 (1.02-1.25) 184 165 Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile.

The WHI estrogen plus progestin substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44-1.07)].

WHI Estrogen-Alone Substudy The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints.

Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years, are presented in Table 7.

Table 7: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI Adapted from numerous WHI publications.

WHI publications can be viewed at www.nhlbi.nih.gov/whi.

Event Relative Risk CE versus Placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

) CE n = 5,310 Placebo n = 5,429 Absolute Risk per 10,000 Women-Years CHD events Results are based on centrally adjudicated data for an average follow-up of 7.1 years.

0.95 (0.78–1.16) 54 57 Non-fatal MI 0.91 (0.73–1.14) 40 43 CHD death 1.01(0.71–1.43) 16 16 All strokes 1.33 (1.05-1.68) 45 33 Ischemic stroke 1.55 (1.19 – 2.01) 38 25 Deep vein thrombosis , Not included in “global index”.

1.47 (1.06–2.06) 23 15 Pulmonary embolism 1.37 (0.90–2.07) 14 10 Invasive breast cancer 0.80 (0.62–1.04) 28 34 Colorectal cancer Results are based on an average follow-up of 6.8 years.

1.08 (0.75–1.55) 17 16 Hip fracture 0.65 (0.45–0.94) 12 19 Vertebral fractures , 0.64 (0.44-0.93) 11 18 Lower arm/wrist fractures , 0.58 (0.47-0.72) 35 59 Total fractures , 0.71 (0.64-0.80) 144 197 Death due to other causes , All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.

1.08 (0.88–1.32) 53 50 Overall mortality , 1.04 (0.88–1.22) 79 75 Global Index A subset of the events was combined in a “global index,” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.

1.02 (0.92–1.13) 206 201 For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.

9 The absolute excess risk of events included in the “global index” was a non-significant 5 events per 10,000 women-years.

There was no difference between the groups in terms of all-cause mortality.

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow up of 7.1 years.

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo.

Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.

10 Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile.

The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)] .

14.6 Women’s Health Initiative Memory Study The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48).

The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years.

Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD).

The most common classification of probable dementia in the treatment group and the placebo group was AD.

Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), and Use in Specific Populations ( 8.5 )].

The WHIMS estrogen-alone ancillary study of WHI study enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66).

The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years.

Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD).

The most common classification of probable dementia in the treatment group and the placebo group was AD.

Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), and Use in Specific Populations ( 8.5 )] .

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60).

Differences between groups became apparent in the first year of treatment.

It is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), and Use in Specific Populations ( 8.5 )].

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied Activella 1 mg/0.5 mg is a white, film-coated tablet, engraved with NOVO 288 on one side and the APIS bull on the other.

It is round, 6mm in diameter and bi-convex.

(NDC 0169-5174-02).

It is supplied as 28 tablets in a calendar dial pack dispenser.

Activella 0.5 mg/0.1 mg is a white, film-coated tablet, engraved with NOVO 291 on one side and the APIS bull on the other.

It is round, 6mm in diameter and bi-convex.

(NDC 0169-5175-10).

It is supplied as 28 tablets in a calendar dial pack dispenser.

16.2 Storage and Handling Store in a dry place protected from light.

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

RECENT MAJOR CHANGES

Contraindications (4) 10/2013 Warnings and Precautions, Hereditary Angioedema (5.15) 10/2013

GERIATRIC USE

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Activella to determine whether those over 65 years of age differ from younger subjects in their response to Activella.

The Women’s Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies ( 14.5 )].

In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies ( 14.5 )].

The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo.

It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.6 )].

Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.6 )].

DOSAGE FORMS AND STRENGTHS

3 Activella tablets are available in two strengths: Each tablet of Activella 1 mg/ 0.5 mg contains 1 mg of estradiol and 0.5 mg of norethindrone acetate.

The tablets are white, round, bi-convex, film-coated tablets engraved with NOVO 288 on one side and the APIS bull on the other.

Each tablet of Activella 0.5 mg/ 0.1 mg contains 0.5 mg of estradiol and 0.1 mg of norethindrone acetate.

The tablets are white, round, bi-convex, film-coated tablets engraved with NOVO 291 on one side and the APIS bull on the other.

Activella (estradiol/norethindrone acetate) 1 mg/0.5 mg tablet (3) Activella (estradiol/norethindrone acetate) 0.5 mg/0.1 mg tablet (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics.

Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle.

After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues.

Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues.

To date, two estrogen receptors have been identified.

These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and FSH through a negative feedback mechanism.

Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen.

Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes.

Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system.

INDICATIONS AND USAGE

1 Activella is an estrogen and progestin combination indicated in a woman with a uterus for: Activella 1 mg/0.5 mg and 0.5 mg/0.1 mg are indicated in a woman with a uterus for: Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 ) Prevention of Postmenopausal Osteoporosis ( 1.3 ) Activella 1 mg/0.5 mg is also indicated in a woman with a uterus for: Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause ( 1.2 ) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Limitation of Use When prescribing solely for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, topical vaginal products should be considered.

1.3 Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.

PEDIATRIC USE

8.4 Pediatric Use Activella is not indicated in children.

Clinical studies have not been conducted in the pediatric population.

PREGNANCY

8.1 Pregnancy Activella should not be used during pregnancy [see Contraindications (4) ].

There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

NUSRING MOTHERS

8.3 Nursing Mothers Activella should not be used during lactation.

Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk.

Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen plus progestin therapy.

Caution should be exercised when Activella is administered to a nursing woman.

BOXED WARNING

WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.5 , 14.6 )].

The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogen (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions ( 5.1 ), and Clinical Studies ( 14.5 )] .

The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo.

It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.6 )].

Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions ( 5.2 ), and Clinical Studies ( 14.5 )] .

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins.

Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.

Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions ( 5.2 )] .

Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions ( 5.1 , 5.3 ), and Clinical Studies ( 14.5 , 14.6 )] .

The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo [see Warnings and Precautions ( 5.1 ), and Clinical Studies ( 14.5 )] .

The WHIMS estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo.

It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.6 )] .

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.

Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER AND PROBABLE DEMENTIA See full prescribing information for complete boxed warning Estrogen Plus Progestin Therapy Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.1 , 5.3 ) The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) ( 5.1 ) The WHI estrogen plus progestin substudy reported increased risks of invasive breast cancer ( 5.2 ) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.3 ) Estrogen-Alone Therapy There is an increased risk of endometrial cancer in a woman with a uterus who use unopposed estrogens ( 5.2 ) Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia ( 5.2 , 5.3 ) The WHI estrogen-alone substudy reported increased risks of stroke and DVT ( 5.1 ) The WHIMS estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older ( 5.3 )

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Estrogens increase the risk of gall bladder disease ( 5.4 ) Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.5 , 5.6 , 5.9 , 5.10 ) Monitor thyroid function in women on thyroid replacement therapy ( 5.11 , 5.18 ) 5.1 Cardiovascular Disorders An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy.

An increased risk of stroke and DVT has been reported with estrogen-alone therapy.

Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.

Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

Stroke In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see Clinical Studies (14.5) ].

The increase in risk was demonstrated after the first year and persisted.

1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years).

The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies ( 14.5 )].

Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.

Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).

1 Coronary Heart Disease In the WHI estrogen plus progestin substudy, there was a statistically non-significant increase risk of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).

1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies ( 14.5 )].

In the WHI estrogen-alone substudy, no overall effect on CHD events was reported in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies ( 14.5 )].

Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).

1 In postmenopausal women with documented heart disease (n=2,763), average 66.7 years of age, in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg plus MPA (2.5 mg) demonstrated no cardiovascular benefit.

During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD.

There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years.

Two thousand, three hundred and twenty‑one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II.

Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall.

Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall.

Venous Thromboembolism In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and PE), was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years).

Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated.

The increase in VTE risk was demonstrated during the first year and persisted 3 [see Clinical Studies ( 14.5 )].

Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

In the WHI estrogen-alone substudy, the risk of VTE was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years).

The increase in VTE risk was demonstrated during the first 2 years 4 [see Clinical Studies ( 14.5 )].

Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

5.2 Malignant Neoplasms Breast Cancer The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg).

After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA.

In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women.

The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo [see Clinical Studies ( 14.5 )].

Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo.

Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years, for CE plus MPA compared with placebo.

In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group.

Metastatic disease was rare, with no apparent difference between the two groups.

Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups 5 [see Clinical Studies ( 14.5 )].

The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone.

In the WHI estrogen-alone substudy, after an average follow‑up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80 6 [see Clinical Studies ( 14.5 )].

Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use.

The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping).

Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy.

However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.

The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.

In a one-year trial among 1,176 women who received either unopposed 1 mg estradiol or a combination of 1 mg estradiol plus one of three different doses of NETA (0.1, 0.25, 0.5 mg), seven new cases of breast cancer were diagnosed, two of which occurred among the group of 295 women treated with Activella 1.0 mg/0.5 mg and two of which occurred among the group of 294 women treated with 1 mg estradiol/0.1 mg NETA.

All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations.

In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

Endometrial Cancer Endometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur at a rate of approximately 1 percent or less with Activella.

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus.

The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose.

Most studies show no significant increased risk associated with use of estrogens for less than 1 year.

The greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24‑fold for 5 to 10 years or more.

This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important.

Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.

Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Ovarian Cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer.

After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24].

The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.

7 In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer.

However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association .

5.3 Probable Dementia In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.

After an average follow-up of 4 years, 40 women in the CE plus MPA and 21 women in the placebo group were diagnosed with probable dementia.

The relative risk of probable dementia for the CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48).

The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years 8 [see Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.6 )].

In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.

After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia.

The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66).

The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years 8 [see Use in Specific Populations (8.5) , and Clinical Studies ( 14.6 )].

When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk of probable dementia was 1.76 (95 percent CI, 1.19-2.60).

Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Use in Specific Populations ( 8.5 ), and Clinical Studies ( 14.6 )].

5.4 Gallbladder Disease A 2- to 4 fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5.5 Hypercalcemia Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases.

If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

5.6 Vision Abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogens.

Discontinue medication pending examination if there is a sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine.

If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.

5.7 Addition of a Progestin When a Woman Has Not Had a Hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone.

Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens.

These include an increased risk of breast cancer.

5.8 Elevated Blood Pressure In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens.

In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen.

5.9 Hypertriglyceridemia In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis.

Consider discontinuation of treatment if pancreatitis occurs.

5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice Estrogens may be poorly metabolized in women with impaired liver function.

For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.

5.11 Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels.

Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T 4 and T 3 serum concentrations in the normal range.

Women dependent on thyroid hormone replacement therapy who are also receiving estrogen may require increased doses of their thyroid replacement therapy.

These women should have their thyroid function monitored to maintain their free thyroid hormone levels in an acceptable range.

5.12 Fluid Retention Estrogens plus progestins may cause some degree of fluid retention.

Women with conditions that might be influenced by this factor, such as a cardiac or renal impairment, warrant careful observation when estrogens plus progestins are prescribed.

5.13 Hypocalcemia Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

5.14 Exacerbation of Endometriosis A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy.

For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

5.15 Hereditary Angioedema Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

5.16 Exacerbation of Other Conditions Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

5.17 Laboratory Tests Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy.

5.18 Drug-Laboratory Test Interactions Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity, increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

Increased TBG levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T 4 levels (by column or by radioimmunoassay), or T 3 levels by radioimmunoassay.

T 3 resin uptake is decreased, reflecting the elevated TBG.

Free T 4 and free T 3 concentrations are unaltered.

Women on thyroid replacement therapy may require higher doses of thyroid hormone.

Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively.

Free hormone concentrations, such as testosterone and estradiol, may be decreased.

Other plasma proteins may be increased (angiotensinogen/rennin substrate, alpha-1 antitrypsin, ceruloplasmin).

Increased plasma high-density lipoprotein (HDL) and HDL 2 cholesterol subfraction concentration, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglyceride levels.

Impaired glucose tolerance.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) 17.1 Abnormal Vaginal Bleeding Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions ( 5.2 )] .

17.2 Possible Serious Adverse Reactions with Estrogen Plus Progestin Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestin therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )].

17.3 Possible Less Serious but Common Adverse Reactions with Estrogen Plus Progestin Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestin therapy such as headache, breast pain and tenderness, nausea and vomiting.

Date of Issue: 10/2013 Rx Only Activella ® is a registered trademark owned by Novo Nordisk FemCare AG © 2000-2013 Novo Nordisk For information contact: Novo Nordisk Inc.

800 Scudders Mill Road Plainsboro, NJ 08536, USA 1-866-668-6336 www.novonordisk-us.com Manufactured by: Novo Nordisk A/S 2880 Bagsvaerd, Denmark

DOSAGE AND ADMINISTRATION

2 Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.

Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.

One tablet to be taken once daily ( 2 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Activella therapy consists of a single tablet to be taken once daily for the treatment of moderate to severe vasomotor symptoms due to menopause.

Activella 1 mg/0.5 mg Activella 0.5 mg/0.1 mg 2.2 Treatment of Moderate to Severe Symptoms of Vulvar and Vaginal Atrophy due to Menopause Activella therapy consists of a single tablet to be taken once daily for the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.

Activella 1 mg/0.5 mg 2.3 Prevention of Postmenopausal Osteoporosis Activella therapy consists of a single tablet to be taken once daily for the prevention of postmenopausal osteoporosis.

Activella 1 mg/0.5 mg Activella 0.5 mg/0.1 mg

RHINOCORT 32 MCG/ACTUAT Metered Dose Nasal Spray

WARNINGS

Warnings Do not use in children under 6 years of age if you have ever had an allergic reaction to any of the ingredients Ask a doctor before use if you have had recent nose ulcers or nose surgery have had a nose injury that has not healed are using a steroid medicine for asthma, allergies or skin rash have an eye infection have or had glaucoma or cataracts When using this product the growth rate of some children may be slower some symptoms may get better on the first day of treatment.

It may take up to two weeks of daily use to feel the most symptom relief.

do not share this bottle with anyone else as this may spread germs remember to tell your doctor about all medicines you take, including this one Stop use and ask a doctor if you have, or come into contact with someone who has chickenpox, measles or tuberculosis you have or develop symptoms of an infection such as persistent fever you have any change in vision you have severe or frequent nosebleeds If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

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

(1-800-222-1222)

INDICATIONS AND USAGE

Uses temporarily relieves these symptoms of hay fever or other upper respiratory allergies: nasal congestion runny nose sneezing itchy nose

INACTIVE INGREDIENTS

Inactive ingredients carboxylmethyl cellulose sodium, dextrose anhydrous, disodium edetate, hydrochloric acid (for pH adjustment), microcrystalline cellulose, polysorbate 80, potassium sorbate, purified water

PURPOSE

Purpose Nasal allergy symptom reliever

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

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

(1-800-222-1222)

ASK DOCTOR

Ask a doctor before use if you have had recent nose ulcers or nose surgery have had a nose injury that has not healed are using a steroid medicine for asthma, allergies or skin rash have an eye infection have or had glaucoma or cataracts

DOSAGE AND ADMINISTRATION

Directions Read instructions (inside package) on how to: get a new bottle ready (primed) before first use prime bottle again if not used for two days use the spray clean the spray nozzle ADULTS AND CHILDREN 12 YEARS OF AGE AND OLDER adults and children 12 years of age and older once daily, spray 2 times into each nostril while sniffing gently once your allergy symptoms improve, reduce to 1 spray in each nostril per day CHILDREN 6 TO UNDER 12 YEARS OF AGE the growth rate of some children may be slower while using this product.

Talk to your child’s doctor if your child needs to use the spray for longer than two months a year.

children 6 to under 12 years of age an adult should supervise use once daily, spray 1 time into each nostril while sniffing gently if allergy symptoms do not improve, increase to 2 sprays in each nostril per day.

Once allergy symptoms improve, reduce to 1 spray in each nostril per day.

children under 6 years of age do not use do not use more than directed if you forget a dose, do not double the next dose do not spray into eyes or mouth if allergy symptoms do not improve after two weeks, stop using and talk to a doctor do not use for the common cold shake well before each use

PREGNANCY AND BREAST FEEDING

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

DO NOT USE

Do not use in children under 6 years of age if you have ever had an allergic reaction to any of the ingredients

STOP USE

Stop use and ask a doctor if you have, or come into contact with someone who has chickenpox, measles or tuberculosis you have or develop symptoms of an infection such as persistent fever you have any change in vision you have severe or frequent nosebleeds

ACTIVE INGREDIENTS

Active ingredient (in each spray) Budesonide (glucocorticoid) 32 mcg

metformin hydrochloride 750 MG 24 HR Extended Release Oral Tablet

DRUG INTERACTIONS

Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with metformin hydrochloride tablets, USP) Glyburide: In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics.

Decreases in glyburide AUC and C max were observed, but were highly variable.

The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION: Concomitant Metformin Hydrochloride Tablets, USP or Metformin Hydrochloride Extended-release Tablets, USP and Oral Sulfonylurea Therapy ).

Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration.

Furosemide increased the metformin plasma and blood C max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance.

When administered with metformin, the C max and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance.

No information is available about the interaction of metformin and furosemide when co-administered chronically.

Nifedipine: A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin C max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine.

T max and half-life were unaffected.

Nifedipine appears to enhance the absorption of metformin.

Metformin had minimal effects on nifedipine.

Cationic drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems.

Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC.

There was no change in elimination half-life in the single-dose study.

Metformin had no effect on cimetidine pharmacokinetics.

Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Other: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.

These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.

When such drugs are administered to a patient receiving metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP, the patient should be closely observed for loss of blood glucose control.

When such drugs are withdrawn from a patient receiving metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP, the patient should be observed closely for hypoglycemia.

In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

OVERDOSAGE

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams.

Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established.

Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS ).

Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions.

Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

DESCRIPTION

Metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP are oral antihyperglycemic drugs used in the management of type 2 diabetes.

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents.

The structural formula is as shown: Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C 4 H 11 N 5 ·HCl and a molecular weight of 165.63.

Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether and chloroform.

The pKa of metformin is 12.4.

The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

Metformin hydrochloride tablets, USP contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride.

Each tablet contains the inactive ingredients magnesium stearate, microcrystalline cellulose and povidone.

In addition, the coating for the 500 mg, 850 mg and 1000 mg tablets contains hypromellose 2910, polyethylene glycol 400 and titanium dioxide.

Metformin hydrochloride extended-release tablets, USP contain 500 mg or 750 mg of metformin hydrochloride as the active ingredient.

Metformin hydrochloride extended-release 500 mg tablets, USP contain the inactive ingredients hypromellose 2208, colloidal silicon dioxide, and magnesium stearate.

Metformin hydrochloride extended-release 750 mg tablets, USP contain the inactive ingredients hypromellose 2208, colloidal silicon dioxide, D&C yellow #10 aluminum lake, and magnesium stearate.

Label

CLINICAL STUDIES

METFORMIN HYDROCHLORIDE TABLETS, USP In a double-blind, placebo-controlled, multicenter U.S.

clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with metformin hydrochloride tablets, USP (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A 1c (HbA 1c ) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2 ).

Table 2.

Metformin Hydrochloride vs.

Placebo Summary of Mean Changes from Baseline* in Plasma Glucose HbA1c and Body Weight, at Final Visit (29-week study) * All patients on diet therapy at Baseline ** Not statistically significant Metformin Hydrochloride (n =141) Placebo (n=145) P-Value FPG (mg/dL) Baseline 241.5 237.7 NS** Change at FINAL VISIT -53.0 6.3 0.001 Hemoglobin A 1c (%) Baseline 8.4 8.2 NS** Change at FINAL VISIT -1.4 0.4 0.001 Body Weight (lbs) Baseline 201.0 206.0 NS** Change at FINAL VISIT -1.4 -2.4 NS** A 29-week, double-blind, placebo-controlled study of metformin hydrochloride tablets, USP and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3 ).

Patients randomized to the combination arm started therapy with metformin hydrochloride tablets, USP 500 mg and glyburide 20 mg.

At the end of each week of the first four weeks of the trial, these patients had their dosages of metformin hydrochloride tablets, USP increased by 500 mg if they had failed to reach target fasting plasma glucose.

After week four, such dosage adjustments were made monthly, although no patient was allowed to exceed metformin hydrochloride tablets, USP 2500 mg.

Patients in the metformin hydrochloride tablets, USP only arm (metformin plus placebo) followed the same titration schedule.

At the end of the trial, approximately 70% of the patients in the combination group were taking metformin hydrochloride tablets, USP 2000 mg/glyburide 20 mg or metformin hydrochloride tablets, USP 2500 mg/glyburide 20 mg.

Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG and HbA 1c of 14 mg/dL, 3 mg/dL and 0.2%, respectively.

In contrast, those randomized to metformin hydrochloride tablets, USP (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG and HbA 1c of 1 mg/dL, 6 mg/dL and 0.4%, respectively.

The combination of metformin hydrochloride tablets, USP and glyburide was effective in reducing FPG, PPG and HbA 1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively.

Compared to results of glyburide treatment alone, the net differences with combination treatment were -77 mg/dL, -68 mg/dL and -1.9%, respectively (see Table 3 ).

Table 3.

Combined Metformin/Glyburide (Comb) vs.

Glyburide (Glyb) or Metformin Hydrochloride (MET) Monotherapy: Summary of Mean Changes from Baseline* in Fasting Plasma Flucose, HbA1c and Body Weight, at Final Visit (29-week study) *All patients on glyburide, 20 mg/day, at Baseline **Not statically significant Comb (n=213) Glyb (n=209) MET (n=210) p-values Glyb vs.

Comb MET vs.

Comb MET vs.

Glyb Fasting Plasma Glucose (mg/dL) Baseline 250.5 247.5 253.9 NS** NS** NS** Change at FINAL VISIT -63.5 13.7 -0.9 0.001 0.001 0.025 Hemoglobin A 1c (%) Baseline 8.8 8.5 8.9 NS** NS** 0.007 Change at FINAL VISIT -1.7 0.2 -0.4 0.001 0.001 0.001 Body Weight (lbs.) Baseline 202.2 203.0 204.0 NS** NS** NS** Change at FINAL VISIT 0.9 -0.7 -8.4 0.011 0.001 0.001 The magnitude of the decline in fasting blood glucose concentration following the institution of metformin hydrochloride tablets, USP therapy was proportional to the level of fasting hyperglycemia.

Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin.

In clinical studies, metformin hydrochloride tablets, USP, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol and LDL cholesterol levels and had no adverse effects on other lipid levels (see Table 4 ).

Table 4.

Summary of Mean Percent Change from Baseline of Major Serum Lipid Variables at Final Visit (29-week studies) Metformin Hydrochloride vs.

Placebo Combined Metformin/ Glyburide vs.

Monotherapy Metformin Hydrochloride (n=141) Placebo (n=145) Metformin Hydrochloride (n=141) Metformin Hydrochloride/ Glyburide (n=213) Glyburide (n=209) Total Cholesterol (mg/dL) Baseline 211.0 212.3 213.1 215.6 219.6 Mean % change at FINAL VISIT -5% 1% -2% -4% 1% Total Triglycerides (mg/dL) Baseline 236.1 203.5 242.5 215.0 266.1 Mean % change at FINAL VISIT -16% 1% -3% -8% 4% LDL-Cholesterol (mg/dL) Baseline 135.4 138.5 134.3 136.0 137.5 Mean % change at FINAL VISIT -8% 1% -4% -6% 3% HDL-Cholesterol (mg/dL) Baseline 39.0 40.5 37.2 39.0 37.0 Mean % change at FINAL VISIT 2% -1% 5% 3% 1% In contrast to sulfonylureas, body weight of individuals on metformin hydrochloride tablets, USP tended to remain stable or even decrease somewhat (see Tables 2 and 3 ).

A 24-week, double-blind, placebo-controlled study of metformin hydrochloride tablets, USP plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 5 ).

Patients randomized to received metformin hydrochloride tablets, USP plus insulin achieved a reduction in HbA 1 c of 2.10%, compared to 1.56% reduction in HbA 1c achieved by insulin plus placebo.

The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs.

110.6 U/day, metformin hydrochloride tablets, USP plus insulin versus insulin plus placebo, respectively P = 0.04.

Table 5.

Combined Metformin Hydrochloride/Insulin vs.

Placebo/Insulin Summary of Mean Changes from Baseline in HbA 1c and Daily Insulin Dose ªStatistically significant using analysis of covariance with baseline as covariate (p=0.04) Not significant using analysis of variance (values shown in table) b Statistically significant for insulin (p=0.04) Metformin Hydrochloride/Insulin (n=26) Placebo/Insulin (n=28) Treatment Difference Mean ± SE Hemoglobin A 1c (%) Baseline 8.95 9.32 Change at FINAL VISIT -2.10 -1.56 -0.54 ± 0.43ª Insulin Dose (U/day) Baseline 93.12 94.64 Change at FINAL VISIT -0.15 15.93 -16.08 ± 7.77 b A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA 1c of 7.46 ± 0.97%, the addition of metformin hydrochloride tablets, USP maintained similar glycemic control (HbA 1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin hydrochloride tablets, USP plus insulin and placebo plus insulin respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for metformin hydrochloride tablets, USP plus insulin and placebo plus insulin, p<0.01).

In addition, this study demonstrated that the combination of metformin hydrochloride tablets, USP plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01.

METFORMIN HYDROCHLORIDE EXTENDED-RELEASE TABLETS, USP A 24-week, double-blind, placebo-controlled study of metformin hydrochloride extended-release tablets, USP, taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA 1c 7.0-10.0%, FPG 126-270 mg/dL).

Patients entering the study had a mean baseline HbA 1c of 8.0% and a mean baseline FPG of 176 mg/dL.

After 12 weeks treatment, mean HbA 1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA 1c of 0.6% and a decrease in mean FPG of 23 mg/dL in patients treated with metformin hydrochloride extended-release tablets, USP 1000 mg once daily.

Subsequently, the treatment dose was increased to 1500 mg once daily if HbA 1c was ≥ 7.0 % but <8.0% (patients with HbA 1c ≥ 8.0% were discontinued from the study).

At the final visit (24-week), mean HbA 1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with metformin hydrochloride extended-release tablets, USP.

A 16-week, double-blind, placebo-controlled, dose-response study of metformin hydrochloride extended-release tablets, USP, taken once daily with the evening meal, or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA 1c 7.0-11.0%, FPG 126-280 mg/dL).

Changes in glycemic control and body weight are shown in Table 6 .

Table 6.

Summary of Mean Changes from Baseline* in HbA 1c , Fasting Plasma Glucose, and Body Weight at Final Visit (16-week study) * All patients on diet therapy at Baseline ª All comparisons versus Placebo ** Not statistically significant Metformin hydrochloride extended-release 500 mg Once Daily 1000 mg Once Daily 1500 mg Once Daily 2000 mg Once Daily 1000 mg Twice Daily Placebo Hemoglobin A 1c (%) (n=115) (n=115) (n=111) (n=125) (n=112) (n=111) Baseline 8.2 8.4 8.3 8.4 8.4 8.4 Change at FINAL VISIT -0.4 -0.6 -0.9 -0.8 -1.1 0.1 p-valueª <0.001 <0.001 <0.001 <0.001 <0.001 – FPG (mg/dL) (n=126) (n=118) (n=120) (n=132) (n=122) (n=113) Baseline 182.7 183.7 178.9 181.0 181.6 179.6 Change at FINAL VISIT -15.2 -19.3 -28.5 -29.9 -33.6 7.6 p-valueª <0.001 <0.001 <0.001 <0.001 <0.001 – Body Weight (lbs) (n=125) (n=119) (n=117) (n=131) (n=119) (n=113) Baseline 192.9 191.8 188.3 195.4 192.5 194.3 Change at FINAL VISIT -1.3 -1.3 -0.7 -1.5 -2.2 -1.8 p-valueª NS** NS** NS** NS** NS** – Compared with placebo, improvement in glycemic control was seen at all dose levels of metformin hydrochloride extended-release tablets, USP and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP).

A 24-week, double-blind, randomized study of metformin hydrochloride extended-release tablets, USP, taken once daily with the evening meal, and metformin hydrochloride tablets, USP, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with metformin hydrochloride tablets, USP 500 mg twice daily for at least 8 weeks prior to study entry.

The metformin hydrochloride tablets, USP dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry.

Patients qualified for the study if HbA 1c was ≤ 8.5 % and FPG was ≤ 200 mg/dL.

Changes in glycemic control and body weight are shown in Table 7 .

Table 7.

Summary of Mean Changes from Baseline* in HbA 1c , Fasting Plasma Glucose, and Body Weight at Week 12 and at Final Visit (24-week study) *All patients on metformin hydrochloride tablets, USP 500 mg twice daily at Baseline ª n=68 Metformin Metformin Hydrochloride Extended-release Tablets, USP Hydrochloride Tablets, USP 500 mg Twice Daily 1000 mg Once Daily 1500 mg Once Daily Hemoglobin A 1c (%) (n=67) (n=72) (n=66) Baseline 7.06 6.99 7.02 Change at 12 Weeks 0.14 0.23 0.04 (95% CI) (-0.03, 0.31) (0.10, 0.36) (-0.08, 0.15) Change at FINAL VISIT 0.14ª 0.27 0.13 (95%) (-0.04, 0.31) (0.11, 0.43) (-0.02, 0.28) FPG (mg/dL) (n=69) (n=72) (n=70) Baseline 127.2 131.0 131.4 Change at 12 Weeks 12.9 9.5 3.7 (95% CI) (6.5, 19.4) (4.4, 14.6) (-0.4, 7.8) Change at FINAL VISIT 14.0 11.5 7.6 (95%) (7.0, 21.0) (4.4, 18.6) (1.0, 14.2) Body Weight (lbs) (n=71) (n=74) (n=71) Baseline 210.3 202.8 192.7 Change at 12 Weeks 0.4 0.9 0.7 (95% CI) (-0.04, 1.5) (0.0, 2.0) (-0.04, 1.8) Change at FINAL VISIT 0.9 1.1 0.9 (95%) (-0.04, 2.2) (-0.2, 2.4) (-0.4, 2.0) After 12 weeks of treatment, there was an increase in mean HbA 1c in all groups; in the metformin hydrochloride extended-release tablets, USP 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION ).

Changes in lipid parameters in the previously described placebo-controlled dose-response study of metformin hydrochloride extended-release tablets, USP are shown in Table 8 .

Table 8.

Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (16-week study) *All patients on diet therapy at Baseline Metformin Hydrochloride Extended-release Tablets, USP 500 mg Once Daily 1000 mg Once Daily 1500 mg Once Daily 2000 mg Once Daily 1000 mg Twice Daily Placebo Total Cholesterol (mg/dL) (n=120) (n=113) (n=110) (n=126) (n=117) (n=110) Baseline 210.3 218.1 214.6 204.4 208.2 208.6 Mean % change at FINAL VISIT 1.0% 1.7% 0.7% -1.6% -2.6% 2.6% Total Triglycerides (mg/dL) (n=120) (n=113) (n=110) (n=126) (n=117) (n=110) Baseline 220.2 211.9 198.0 194.2 179.0 211.7 Mean % change at FINAL VISIT 14.5% 9.4% 15.1% 14.9% 9.4% 10.9% LDL-Cholesterol (mg/dL) (n=119) (n=113) (n=109) (n=126) (n=117) (n=107) Baseline 131.0 134.9 135.8 125.8 131.4 131.9 Mean % change at FINAL VISIT -1.4% -1.6% -3.5% -3.3% -5.5% 3.2% HDL-Cholesterol (mg/dL) (n=120) (n=108) (n=108) (n=125) (n=117) (n=108) Baseline 40.8 41.6 40.6 40.2 42.4 39.4 Mean % change at FINAL VISIT 6.2% 8.6% 5.5% 6.1% 7.1% 5.8% Changes in lipid parameters in the previously described study of metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP are shown in Table 9 .

Table 9.

Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (24-week study) *All patients on metformin hydrochloride tablets, USP 500 mg twice daily at Baseline Metformin Hydrochloride Tablets, USP Metformin Hydrochloride Extended-release Tablets, USP 500 mg Twice Daily 1000 mg Once Daily 1500 mg Once Daily Total Cholesterol (mg/dL) (n=68) (n=70) (n=66) Baseline 199.0 201.9 201.6 Mean % change at FINAL VISIT 0.1% 1.3% 0.1% Total Triglycerides (mg/dL) (n=68) (n=70) (n=66) Baseline 178.0 169.2 206.8 Mean % change at FINAL VISIT 6.3% 25.3% 33.4% LDL-Cholesterol (mg/dL) (n=68) (n=70) (n=66) Baseline 122.1 126.2 115.7 Mean % change at FINAL VISIT -1.3% -3.3% -3.7% HDL-Cholesterol (mg/dL) (n=68) (n=70) (n=65) Baseline 41.9 41.7 44.6 Mean % change at FINAL VISIT 4.8% 1.0% -2.1% Pediatric Clinical Studies In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with metformin hydrochloride tablets, USP (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 10 ).

Table 10.

Metformin Hydrochloride Tablets, USP vs.

Placebo (Pediatricsª) Summary of Mean Changes from Baseline* in Plasma Glucose and Body Weight at Final Visit ª Pediatric patients mean age 13.8 years (range 10-16 years) * All patients on diet therapy at Baseline ** Not statistically significant Metformin Hydrochloride Tablets, USP Placebo p-Value FPG (mg/dL) (n=37) (n=36) Baseline 162.4 192.3 Change at FINAL VISIT -42.9 21.4 <0.001 Body Weight (lbs) (n=39) (n=38) Baseline 205.3 189.0 Change at FINAL VISIT -3.3 -2.0 NS**

HOW SUPPLIED

Metformin hydrochloride tablets, USP are available as: 500 mg Bottles of 100 NDC 62037-674-01 500 mg Bottles of 500 NDC 62037-674-05 500 mg Bottles of 1000 NDC 62037-674-10 850 mg Bottles of 100 NDC 62037-675-01 850 mg Bottles of 500 NDC 62037-675-05 850 mg Bottles of 1000 NDC 62037-675-10 1000 mg Bottles of 100 NDC 62037-676-01 1000 mg Bottles of 500 NDC 62037-676-05 1000 mg Bottles of 1000 NDC 62037-676-10 Metformin hydrochloride 500 mg tablets, USP are round, white to off-white, film coated tablets debossed with “Andrx 674” on one side and “500” debossed on the other side.

Metformin hydrochloride 850 mg tablets, USP are round, white to off-white, film coated tablets debossed with “Andrx 675” on one side and “850” debossed on the other side.

Metformin hydrochloride 1000 mg tablets, USP are oval, white to off-white, film coated tablets with “Andrx 676” debossed on one side and bisected “1000” on the other side.

Metformin hydrochloride extended-release tablets, USP are available as: 500 mg Bottles of 90 NDC 62037-571-90 500 mg Bottles of 100 NDC 62037-571-01 500 mg Bottles of 500 NDC 62037-571-05 500 mg Bottles of 1000 NDC 62037-571-10 750 mg Bottles of 100 NDC 62037-577-01 750 mg Bottles of 500 NDC 62037-577-05 750 mg Bottles of 1000 NDC 62037-577-10 Metformin hydrochloride extended-release 500 mg tablets, USP are white to off-white, capsule shaped tablets, debossed with the and “571” on one side and “500” on the other side.

Metformin hydrochloride extended-release 750 mg tablets, USP are light yellow, capsule shaped tablets, debossed with and “577” on one side and “750” on opposite side.

Logo Logo Storage Store at controlled room temperature 20°-25°C (68°-77°F).

[See USP.] Dispense in light-resistant containers.

Metformin hydrochloride tablets, USP are manufactured by: Patheon Puerto Rico, Inc.

Caguas, Puerto Rico 00725, USA Distributed by: Watson Pharma, Inc.

Metformin hydrochloride extended-release tablets, USP are manufactured by: Watson Laboratories, Inc.

Corona, CA 92880 USA Distributed by: Watson Pharma, Inc.

Rev.

date 05/09 190733

GERIATRIC USE

Geriatric Use Controlled clinical studies of metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, metformin hydrochloride tablets, USP, and metformin hydrochloride extended-release tablets, USP should only be used in patients with normal renal function (see CONTRAINDICATIONS , WARNINGS and CLINICAL PHARMACOLOGY: Pharmacokinetics ).

Because aging is associated with reduced renal function, metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP should be used with caution as age increases.

Care should be taken in dose selection and should be based on careful and regular monitoring of renal function.

Generally, elderly patients should not be titrated to the maximum dose of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP (see also WARNINGS and DOSAGE AND ADMINISTRATION ).

MECHANISM OF ACTION

Mechanism of Action Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose.

Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents.

Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS ) and does not cause hyperinsulinemia.

With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

INDICATIONS AND USAGE

Metformin hydrochloride tablets, USP is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.

Metformin hydrochloride extended-release tablets, USP is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

PEDIATRIC USE

Pediatric Use The safety and effectiveness of metformin hydrochloride tablets, USP for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years).

Use of metformin hydrochloride tablets, USP in this age group is supported by evidence from adequate and well-controlled studies of metformin hydrochloride tablets, USP in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults.

(See CLINICAL PHARMACOLOGY: Pediatric Clinical Studies.

) In this study, adverse effects were similar to those described in adults.

(See ADVERSE REACTIONS: Pediatric Patients.

) A maximum daily dose of 2000 mg is recommended.

(See DOSAGE AND ADMINISTRATION: Recommended Dosing Schedule: Pediatrics .

) Safety and effectiveness of metformin hydrochloride extended-release tablets, USP in pediatric patients have not been established.

PREGNANCY

Pregnancy Teratogenic Effects: Pregnancy Category B.

Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities.

Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Because animal reproduction studies are not always predictive of human response, metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP should not be used during pregnancy unless clearly needed.

There are no adequate and well-controlled studies in pregnant women with metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP.

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day.

This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively.

Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

NUSRING MOTHERS

Nursing Mothers Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma.

Similar studies have not been conducted in nursing mothers.

Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

If metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP are discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

BOXED WARNING

WARNINGS Lactic Acidosis : Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP; when it occurs, it is fatal in approximately 50% of cases.

Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia.

Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio.

When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years).

In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis.

Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.

Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis.

The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age.

The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP and by use of the minimum effective dose of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP.

In particular, treatment of the elderly should be accompanied by careful monitoring of renal function.

Metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis.

In addition, metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.

Because impaired hepatic function may significantly limit the ability to clear lactate, metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism.

In addition, metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS ).

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis.

The patient and the patient’s physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS ).

Metformin hydrochloride tablets, USP and metformin hydrochloride extended-release tablets, USP should be withdrawn until the situation is clarified.

Serum electrolytes, ketones, blood glucose and- if indicated, blood pH, lactate levels, and even blood metformin levels may be useful.

Once a patient is stabilized on any dose level of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related.

Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.

(See also PRECAUTIONS.

) Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting.

In a patient with lactic acidosis who is taking metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP, the drug should be discontinued immediately and general supportive measures promptly instituted.

Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin.

Such management often results in prompt reversal of symptoms and recovery.

(See also CONTRAINDICATIONS and PRECAUTIONS .)

INFORMATION FOR PATIENTS

Information for Patients Patients should be informed of the potential risks and benefits of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP and of alternative modes of therapy.

They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function and hematologic parameters.

The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients.

Patients should be advised to discontinue metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence or other nonspecific symptoms occur.

Once a patient is stabilized on any dose level of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related.

Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP.

Metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP alone does not usually cause hypoglycemia, although it may occur when metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP are used in conjunction with oral sulfonylureas and insulin.

When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients.

(See Patient Information Printed Separately.) Patients should be informed that metformin hydrochloride extended-release tablets, USP must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

DOSAGE AND ADMINISTRATION

There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP or any other pharmacologic agent.

Dosage of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily dose.

The maximum recommended daily dose of metformin hydrochloride tablets, USP is 2550 mg in adults and 2000 mg in pediatric patients (10-16 years of age); the maximum recommended daily dose of metformin hydrochloride extended-release tablets, USP in adults is 2000 mg.

Metformin hydrochloride tablets, USP should be given in divided doses with meals while metformin hydrochloride extended-release tablets, USP should generally be given once daily with the evening meal.

Metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.

During treatment initiation and dose titration (see Recommended Dosing Schedule ), fasting plasma glucose should be used to determine the therapeutic response to metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP and identify the minimum effective dose for the patient.

Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months.

The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP, either when used as monotherapy or in combination with sulfonylurea or insulin.

Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness.

Short-term administration of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

Metformin hydrochloride extended-release tablets, USP must be swallowed whole and never crushed or chewed.

Occasionally, the inactive ingredients of metformin hydrochloride extended-release will be eliminated in the feces as a soft, hydrated mass.

(See Patient Information printed separately.) Recommended Dosing Schedule Adults – In general, clinically significant responses are not seen at doses below 1500 mg per day.

However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.

The usual starting dose of metformin hydrochloride tablets, USP is 500 mg twice a day or 850 mg once a day, given with meals.

Dosage increases should be made in increment of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses.

Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks.

For those patients requiring additional glycemic control, metformin hydrochloride tablets, USP may be given to a maximum daily dose of 2550 mg per day.

Doses above 2000 mg may be better tolerated given three times a day with meals.

The usual starting dose of metformin hydrochloride extended-release tablets, USP is 500 mg once daily with the evening meal.

Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal.

If glycemic control is not achieved on metformin hydrochloride extended-release tablets, USP 2000 mg once daily, a trial of metformin hydrochloride extended-release tablets, USP 1000 mg twice daily should be considered.

If higher doses of metformin hydrochloride tablets, USP are required, metformin hydrochloride tablets, USP should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above.

(See CLINICAL PHARMACOLOGY, Clinical Studies .) In a randomized trial, patients currently treated with metformin hydrochloride tablets, USP were switched to metformin hydrochloride extended-release tablets, USP.

Results of this trial suggest that patients receiving metformin hydrochloride tablets, USP treatment may be safely switched to metformin hydrochloride extended-release tablets, USP once daily at the same total daily dose, up to 2000 mg once daily.

Following a switch from metformin hydrochloride tablets, USP to metformin hydrochloride extended-release tablets, USP glycemic control should be closely monitored and dosage adjustments made accordingly (see CLINICAL PHARMACOLOGY, Clinical Studies ).

Pediatrics – The usual starting dose of metformin hydrochloride tablets, USP is 500 mg twice a day, given with meals.

Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses.

Safety and effectiveness of metformin hydrochloride extended-release tablets, USP in pediatric patients have not been established.

Transfer from Other Antidiabetic Therapy When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP no transition period generally is necessary.

When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.

Concomitant Metformin Hydrochloride Tablets, USP or Metformin Hydrochloride Extended-release Tablets, USP and Oral Sulfonylurea Therapy in Adult Patients If patients have not responded to four weeks of the maximum dose of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin hydrochloride tablets, USP or metformin hydrochloride extendedrelease tablets, USP at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred.

Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide).

With concomitant metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug.

In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on metformin hydrochloride tablets, USP 500 mg and glyburide 20 mg were titrated to 1000/20mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of metformin hydrochloride tablets, USP and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA 1c and plasma glucose response (see CLINICAL PHARMACOLOGY: Clinical Studies ).

However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal.

With concomitant metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased.

Appropriate precautions should be taken.

(See Package Insert of the respective sulfonylurea.) If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP.

Concomitant Metformin Hydrochloride Tablets, USP or Metformin Hydrochloride Extended-release Tablets, USP and Insulin Therapy in Adult Patients The current insulin dose should be continued upon initiation of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP therapy.

Metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP should be initiated at 500 mg once daily in patients on insulin therapy.

For patients not responding adequately, the dose of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved.

The maximum recommended daily dose is 2500 mg for metformin hydrochloride tablets, USP and 2000 mg for metformin hydrochloride extended-release tablets, USP.

It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and metformin hydrochloride tablets, USP or metformin hydrochlorideextended-release tablets, USP.

Further adjustment should be individualized based on glucose-lowering response.

Specific Patient Populations Metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP are not recommended for use in pregnancy.

Metformin hydrochloride tablets, USP are not recommended in patients below the age of 10 years.

Metformin hydrochloride extended-release tablets, USP are not recommended in pediatric patients (below the age of 17 years).

The initial and maintenance dosing of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP should be conservative in patients with advanced age, due to the potential for decreased renal function in this population.

Any dosage adjustment should be based on a careful assessment of renal function.

Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of metformin hydrochloride tablets, USP or metformin hydrochloride extended-release tablets, USP.

Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly.

(See WARNINGS .)

palonosetron 0.25 MG in 5 ML Injection

DRUG INTERACTIONS

7 Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes.

Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and, CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5.

Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low.

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) [ see Warnings and Precautions (5.2) ].

Coadministration of 0.25 mg I.V.

palonosetron and 20 mg I.V.

dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.

In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V.

bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, C max : 15% increase).

A study in healthy volunteers involving single-dose I.V.

palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.

In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.

Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin, and mitomycin C) in murine tumor models.

The potential for clinically significant drug interactions with palonosetron appears to be low ( 7 )

OVERDOSAGE

10 There is no known antidote to ALOXI.

Overdose should be managed with supportive care.

Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study.

This is approximately 25 times the recommended dose of 0.25 mg.

This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed.

Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose.

A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice.

The major signs of toxicity were convulsions, gasping, pallor, cyanosis, and collapse.

DESCRIPTION

11 ALOXI (palonosetron hydrochloride) is an antiemetic and antinauseant agent.

It is a serotonin-3 (5-HT 3 ) receptor antagonist with a strong binding affinity for this receptor.

Chemically, palonosetron hydrochloride is: (3a S) -2-[( S )-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1 H benz[ de ]isoquinoline hydrochloride.

The empirical formula is C 19 H 24 N 2 O.HCl, with a molecular weight of 332.87.

Palonosetron hydrochloride exists as a single isomer and has the following structural formula: Palonosetron hydrochloride is a white to off-white crystalline powder.

It is freely soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and 2-propanol.

ALOXI injection is a sterile, clear, colorless, nonpyrogenic, isotonic, buffered solution for intravenous administration.

ALOXI injection is available as 5 mL single use vial or 1.5 mL single use vial.

Each 5 mL vial contains 0.25 mg palonosetron base as 0.28 mg palonosetron hydrochloride, 207.5 mg mannitol, disodium edetate and citrate buffer in water for intravenous administration.

Each 1.5 mL vial contains 0.075 mg palonosetron base as 0.084 mg palonosetron hydrochloride, 62.25 mg mannitol, disodium edetate and citrate buffer in water for intravenous administration.

The pH of the solution in the 5 mL and 1.5 mL vials is 4.5 to 5.5.

The structural formula for serotonin-3 (5-HT3) is a receptor antagonist with a strong binding affinity for this receptor.

Chemically, palonosetron hydrochloride is: (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1Hbenz[de]isoquinoline hydrochloride.

The empirical formula is C19H24N2O.HCl, with a molecular weight of 332.87.

CLINICAL STUDIES

14 97.5% Confidence Interval ALOXI minus Comparator c 97.5% Confidence Interval ALOXI minus Comparator c 97.5% Confidence Interval ALOXI minus Comparator c 14.1 Chemotherapy-Induced Nausea and Vomiting in Adults Efficacy of single-dose palonosetron injection in preventing acute and delayed nausea and vomiting induced by both moderately and highly emetogenic chemotherapy was studied in three Phase 3 trials and one Phase 2 trial.

In these double-blind studies, complete response rates (no emetic episodes and no rescue medication) and other efficacy parameters were assessed through at least 120 hours after administration of chemotherapy.

The safety and efficacy of palonosetron in repeated courses of chemotherapy was also assessed.

Moderately Emetogenic Chemotherapy Two Phase 3, double-blind trials involving 1132 patients compared single-dose I.V.

ALOXI with either single-dose I.V.

ondansetron (study 1) or dolasetron (study 2) given 30 minutes prior to moderately emetogenic chemotherapy including carboplatin, cisplatin ≤ 50 mg/m², cyclophosphamide 25 mg/m², epirubicin, irinotecan, and methotrexate > 250 mg/m².

Concomitant corticosteroids were not administered prophylactically in study 1 and were only used by 4-6% of patients in study 2.

The majority of patients in these studies were women (77%), White (65%) and naïve to previous chemotherapy (54%).

The mean age was 55 years.

Highly Emetogenic Chemotherapy A Phase 2, double-blind, dose-ranging study evaluated the efficacy of single-dose I.V.

palonosetron from 0.3 to 90 mcg/kg (equivalent to 1100 mg/m²).

Concomitant corticosteroids were not administered prophylactically.

Analysis of data from this trial indicates that 0.25 mg is the lowest effective dose in preventing acute nausea and vomiting induced by highly emetogenic chemotherapy.

A Phase 3, double-blind trial involving 667 patients compared single-dose I.V.

ALOXI with single-dose I.V.

ondansetron (study 3) given 30 minutes prior to highly emetogenic chemotherapy including cisplatin ≥ 60 mg/m², cyclophosphamide > 1500 mg/m², and dacarbazine.

Corticosteroids were co-administered prophylactically before chemotherapy in 67% of patients.

Of the 667 patients, 51% were women, 60% White, and 59% naïve to previous chemotherapy.

The mean age was 52 years.

Efficacy Results The antiemetic activity of ALOXI was evaluated during the acute phase (0-24 hours) [Table 4], delayed phase (24-120 hours) [Table 5], and overall phase (0-120 hours) [Table 6] post-chemotherapy in Phase 3 trials.

Table 4: Prevention of Acute Nausea and Vomiting (0-24 hours): Complete Response Rates Chemotherapy Study Treatment Group N a % with Complete Response p-value b 97.5% Confidence Interval ALOXI minus Comparator c Moderately Emetogenic 1 ALOXI 0.25 mg 189 81 0.009 Ondansetron 32 mg I.V.

185 69 2 ALOXI 0.25 mg 189 63 NS Dolasetron 100 mg I.V.

191 53 Highly Emetogenic 3 ALOXI 0.25 mg 223 59 NS Difference in Complete Response Rates Ondansetron 32 mg I.V.

221 57 a Intent-to-treat cohort b 2-sided Fisher’s exact test.

Significance level at α=0.025.

c These studies were designed to show non-inferiority.

A lower bound greater than –15% demonstrates non-inferiority between ALOXI and comparator.

These studies show that ALOXI was effective in the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy.

In study 3, efficacy was greater when prophylactic corticosteroids were administered concomitantly.

Clinical superiority over other 5-HT 3 receptor antagonists has not been adequately demonstrated in the acute phase.

Table 5: Prevention of Delayed Nausea and Vomiting (24-120 hours): Complete Response Rates Chemotherapy Study Treatment Group N a % with Complete Response p-value b 97.5% Confidence Interval ALOXI minus Comparator c Moderately Emetogenic 1 ALOXI 0.25 mg 189 74 <0.001 Ondansetron 32 mg I.V.

185 55 2 ALOXI 0.25 mg 189 54 0.004 Dolasetron 100 mg I.V.

191 39 Difference in Complete Response Rates a Intent-to-treat cohort b 2-sided Fisher’s exact test.

Significance level at α=0.025.

c These studies were designed to show non-inferiority.

A lower bound greater than –15% demonstrates non-inferiority between ALOXI and comparator.

These studies show that ALOXI was effective in the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy.

Table 6: Prevention of Overall Nausea and Vomiting (0-120 hours): Complete Response Rates Chemotherapy Study Treatment Group N a % with Complete Response p-value b 97.5% Confidence Interval ALOXI minus Comparator c Moderately Emetogenic 1 ALOXI 0.25 mg 189 69 <0.001 Ondansetron 32 mg I.V.

185 50 2 ALOXI 0.25 mg 189 46 0.021 Dolasetron 100 mg I.V.

191 34 Difference in Complete Response Rates a Intent-to-treat cohort b 2-sided Fisher’s exact test.

Significance level at α=0.025.

c These studies were designed to show non-inferiority.

A lower bound greater than –15% demonstrates non inferiority between ALOXI and comparator.

These studies show that ALOXI was effective in the prevention of nausea and vomiting throughout the 120 hours (5 days) following initial and repeat courses of moderately emetogenic cancer chemotherapy.

14.2 Chemotherapy-Induced Nausea and Vomiting in Pediatrics One double-blind, active-controlled clinical trial was conducted in pediatric cancer patients.

The total population (N = 327) had a mean age of 8.3 years (range 2 months to 16.9 years) and were 53% male; and 96% white.

Patients were randomized and received a 20 mcg/kg (maximum 1.5 mg) intravenous infusion of ALOXI 30 minutes prior to the start of emetogenic chemotherapy (followed by placebo infusions 4 and 8 hours after the dose of palonosetron) or 0.15 mg/kg of intravenous ondansetron 30 minutes prior to the start of emetogenic chemotherapy (followed by ondansetron 0.15 mg/kg infusions 4 and 8 hours after the first dose of ondansetron, with a maximum total dose of 32 mg).

Emetogenic chemotherapies administered included doxorubicin, cyclophosphamide (<1500 mg/m 2 ), ifosfamide, cisplatin, dactinomycin, carboplatin, and daunorubicin.

Adjuvant corticosteroids, including dexamethasone, were administered with chemotherapy in 55% of patients.

Complete Response in the acute phase of the first cycle of chemotherapy was defined as no vomiting, no retching, and no rescue medication in the first 24 hours after starting chemotherapy.

Efficacy was based on demonstrating non-inferiority of intravenous palonosetron compared to intravenous ondansetron.

Non-inferiority criteria were met if the lower bound of the 97.5% confidence interval for the difference in Complete Response rates of intravenous palonosetron minus intravenous ondansetron was larger than -15%.

The non-inferiority margin was 15%.

Efficacy Results As shown in Table 7, intravenous ALOXI 20 mcg/kg (maximum 1.5 mg) demonstrated non-inferiority to the active comparator during the 0 to 24 hour time interval.

Table 7: Prevention of Acute Nausea and Vomiting (0-24 hours): Complete Response Rates I.V.

ALOXI 20 mcg/kg (N=165) I.V.

Ondansetron 0.15 mg/kg x 3 (N=162) Difference [97.5% Confidence Interval]*: I.V.

ALOXI minus I.V.

Ondansetron Comparator 59.4% 58.6% 0.36% [-11.7%, 12.4%] * To adjust for multiplicity of treatment groups, a lower-bound of a 97.5% confidence interval was used to compare to -15%, the negative value of the non-inferiority margin.

In patients that received ALOXI at a lower dose than the recommended dose of 20 mcg/kg, non-inferiority criteria were not met.

14.3 Postoperative Nausea and Vomiting In one multicenter, randomized, stratified, double-blind, parallel-group, phase 3 clinical study (Study 1), palonosetron was compared with placebo for the prevention of PONV in 546 patients undergoing abdominal and gynecological surgery.

All patients received general anesthesia.

Study 1 was a pivotal study conducted predominantly in the US in the out-patient setting for patients undergoing elective gynecologic or abdominal laparoscopic surgery and stratified at randomization for the following risk factors: gender, non-smoking status, history of post operative nausea and vomiting and/or motion sickness.

In Study 1 patients were randomized to receive palonosetron 0.025 mg, 0.050 mg or 0.075 mg or placebo, each given intravenously immediately prior to induction of anesthesia.

The antiemetic activity of palonosetron was evaluated during the 0 to 72 hour time period after surgery.

Of the 138 patients treated with 0.075 mg palonosetron in Study 1 and evaluated for efficacy, 96% were women; 66% had a history of PONV or motion sickness; 85% were non-smokers.

As for race, 63% were White, 20% were Black, 15% were Hispanic, and 1% were Asian.

The age of patients ranged from 21 to 74 years, with a mean age of 37.9 years.

Three patients were greater than 65 years of age.

Co-primary efficacy measures were Complete Response (CR) defined as no emetic episode and no use of rescue medication in the 0-24 and in the 24-72 hours postoperatively.

Secondary efficacy endpoints included: Complete Response (CR) 0-48 and 0-72 hours Complete Control (CC) defined as CR and no more than mild nausea Severity of nausea (none, mild, moderate, severe) The primary hypothesis in Study 1 was that at least one of the three palonosetron doses were superior to placebo.

Results for Complete Response in Study 1 for 0.075 mg palonosetron versus placebo are described in the following table.

Table 8: Prevention of Postoperative Nausea and Vomiting: Complete Response (CR), Study 1, Palonosetron 0.075 mg Vs Placebo Treatment n/N (%) Palonosetron Vs Placebo Δ p-value* Co-primary Endpoints CR 0-24 hours Palonosetron 59/138 (42.8%) 16.8% 0.004 Placebo 35/135 (25.9%) CR 24-72 hours Palonosetron 67/138 (48.6%) 7.8% 0.188 Placebo 55/135 (40.7%) * To reach statistical significance for each co-primary endpoint, the required significance limit for the lowest p-value was p<0.017.

Δ Difference (%): palonosetron 0.075 mg minus placebo Palonosetron 0.075 mg reduced the severity of nausea compared to placebo.

Analyses of other secondary endpoints indicate that palonosetron 0.075 mg was numerically better than placebo, however, statistical significance was not formally demonstrated.

A phase 2 randomized, double-blind, multicenter, placebo-controlled, dose ranging study was performed to evaluate I.V.

palonosetron for the prevention of post-operative nausea and vomiting following abdominal or vaginal hysterectomy.

Five I.V.

palonosetron doses (0.1, 0.3, 1.0, 3.0, and 30 µg/kg) were evaluated in a total of 381 intent-to-treat patients.

The primary efficacy measure was the proportion of patients with CR in the first 24 hours after recovery from surgery.

The lowest effective dose was palonosetron 1 µg/kg (approximately 0.075 mg) which had a CR rate of 44% versus 19% for placebo, p=0.004.

Palonosetron 1 µg/kg also significantly reduced the severity of nausea versus placebo, p=0.009.

HOW SUPPLIED

16 /STORAGE AND HANDLING NDC # 62856-797-01, ALOXI Injection 0.25 mg/5 mL (free base) single-use vial individually packaged in a carton.

NDC # 62856-798-01, ALOXI Injection 0.075 mg/1.5 mL (free base) single-use vial packaged in a carton containing 5 vials.

Storage Store at controlled temperature of 20–25°C (68°F–77°F).

Excursions permitted to 15–30°C (59-86°F).

Protect from freezing.

Protect from light.

RECENT MAJOR CHANGES

Indication ( 1.2 ) Dosage and Administration, Pediatric Cancer Patients ( 2.1 ) Warnings and Precautions, Serotonin Syndrome ( 5.2 ) 05/2014 05/2014 09/2014

GERIATRIC USE

8.5 Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years).

Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old.

No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out.

No dose adjustment or special monitoring are required for geriatric patients.

Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old.

No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded.

No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients.

However, ALOXI efficacy in geriatric patients has not been adequately evaluated.

DOSAGE FORMS AND STRENGTHS

3 ALOXI is supplied as a single-use sterile, clear, colorless solution in glass vials that provide: 0.25 mg (free base) per 5 mL (concentration: 0.05 mg/mL, 50 mcg/mL) 0.075 mg (free base) per 1.5 mL (concentration: 0.05 mg/mL, 50 mcg/mL) 0.25 mg/5mL (free base) single-use vial ( 3 ) 0.075 mg/1.5mL (free base) single-use vial ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Palonosetron is a 5-HT 3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors.

Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used.

5-HT 3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema.

It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT 3 receptors located on vagal afferents to initiate the vomiting reflex.

Postoperative nausea and vomiting is influenced by multiple patient, surgical, and anesthesia related factors and is triggered by release of 5-HT in a cascade of neuronal events involving both the central nervous system and the gastrointestinal tract.

The 5-HT 3 receptor has been demonstrated to selectively participate in the emetic response.

INDICATIONS AND USAGE

1 ALOXI is a serotonin-3 (5-HT 3 ) receptor antagonist indicated in adults for: Moderately emetogenic cancer chemotherapy — prevention of acute and delayed nausea and vomiting associated with initial and repeat courses ( 1.1 ) Highly emetogenic cancer chemotherapy — prevention of acute nausea and vomiting associated with initial and repeat courses ( 1.1 ) Prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery.

Efficacy beyond 24 hours has not been demonstrated ( 1.3 ) ALOXI is indicated in pediatric patients aged 1 month to less than 17 years for: Prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy ( 1.2 ) 1.1 Chemotherapy -Induced Nausea and Vomiting in Adults ALOXI is indicated for: Moderately emetogenic cancer chemotherapy — prevention of acute and delayed nausea and vomiting associated with initial and repeat courses Highly emetogenic cancer chemotherapy — prevention of acute nausea and vomiting associated with initial and repeat courses 1.2 Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients Aged 1 M onth to Less than 17 Years ALOXI is indicated for prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy.

1.3 Postoperative Nausea and Vo miting in Adults ALOXI is indicated for prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery.

Efficacy beyond 24 hours has not been demonstrated.

As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively.

In patients where nausea and vomiting must be avoided during the postoperative period, ALOXI is recommended even where the incidence of postoperative nausea and/or vomiting is low.

PEDIATRIC USE

8.4 Pediatric Use Chemotherapy-Induced Nausea and Vomiting Safety and effectiveness of ALOXI have been established in pediatric patients aged 1 month to less than 17 years for the prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy.

Use is supported by a clinical trial where 165 pediatric patients aged 2 months to <17 years were randomized to receive a single dose of palonosetron 20 mcg/kg (maximum 1.5 mg) administered as an intravenous infusion 30 minutes prior to the start of emetogenic chemotherapy [ see Clinical Studies (14.2) ] .

While this study demonstrated that pediatric patients require a higher palonosetron dose than adults to prevent chemotherapy-induced nausea and vomiting, the safety profile is consistent with the established profile in adults [ see Adverse Reactions (6.1) ] .

Safety and effectiveness of ALOXI in neonates (less than 1 month of age) have not been established.

Postoperative Nausea and Vomiting Studies Safety and efficacy have not been established in pediatric patients for prevention of postoperative nausea and vomiting.

Two pediatric trials were performed.

Pediatric Study 1, a dose finding study, was conducted to compare two doses of palonosetron, 1 mcg/kg (max 0.075 mg) versus 3 mcg/kg (max 0.25 mg).

A total of 150 pediatric surgical patients participated, age range 1 month to <17 years.

No dose response was observed.

Pediatric Study 2, a multicenter, double-blind, double-dummy, randomized, parallel group, active control, single-dose non-inferiority study, compared I.V.

palonosetron (1 mcg/kg, max 0.075 mg) versus I.V.

ondansetron.

A total of 670 pediatric surgical patients participated, age 30 days to <17 years.

The primary efficacy endpoint, Complete Response (CR: no vomiting, no retching, and no antiemetic rescue medication) during the first 24 hours postoperatively was achieved in 78.2% of patients in the palonosetron group and 82.7% in the ondansetron group.

Given the pre-specified non-inferiority margin of -10%, the stratum adjusted Mantel-Haenszel statistical non-inferiority confidence interval for the difference in the primary endpoint, complete response (CR), was [-10.5, 1.7%], therefore non-inferiority was not demonstrated.

Adverse reactions to palonosetron were similar to those reported in adults (Table 2).

PREGNANCY

8.1 Pregnancy Pregnancy Category B Risk Summary Adequate and well controlled studies with ALOXI have not been conducted in pregnant women.

In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral palonosetron during the period of organogenesis at doses up to 1894 and 3789 times the recommended human intravenous dose in rats and rabbits, respectively.

Because animal reproduction studies are not always predictive of human response, ALOXI should be used during pregnancy only if clearly needed.

Animal Data In animal studies, no effects on embryo-fetal development were observed in pregnant rats given oral palonosetron at doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (3789 times the recommended human intravenous dose based on body surface area) during the period of organogenesis.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether ALOXI is present in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study [ see Nonclinical Toxicology (13.1) ] , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other selective 5-HT 3 receptor antagonists ( 5.1 ) Serotonin syndrome has been reported with 5-HT 3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs ( 5.2 ) 5.1 Hypersensitivity Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other 5-HT 3 receptor antagonists.

5.2 Serotonin Syndrome The development of serotonin syndrome has been reported with 5-HT 3 receptor antagonists.

Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue).

Some of the reported cases were fatal.

Serotonin syndrome occurring with overdose of another 5-HT 3 receptor antagonist alone has also been reported.

The majority of reports of serotonin syndrome related to 5-HT 3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of ALOXI and other serotonergic drugs.

If symptoms of serotonin syndrome occur, discontinue ALOXI and initiate supportive treatment.

Patients should be informed of the increased risk of serotonin syndrome, especially if ALOXI is used concomitantly with other serotonergic drugs [see Drug Interactions (7), Patient Counseling Information (17) ] .

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labelling ( Patient Information ).

Instructions for Patients Patients should be advised to report to their physician all of their medical conditions, including any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6.3) ].

Advise patients of the possibility of serotonin syndrome, especially with concomitant use of ALOXI and another serotonergic agent such as medications to treat depression and migraines.

Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms [ see Warnings and Precautions (5.2) ].

Patients should be instructed to read the Patient Information.

DOSAGE AND ADMINISTRATION

2 Chemotherapy-Induced Nausea and Vomiting ( 2.1 ) Age Dose* Infusion Time Adults 0 .

2 5 m g x 1 Infuse over 3 0 s e c o nd s beginning approx.

30 min before the start of chemo Pediatrics (1 month to less than 17 years) 2 0 m icr o g r a m s p er k il o g r a m (max 1.5 mg) x 1 Infuse over 1 5 m i nut es beginning approx.

30 min before the start of chemo *Note different dosing units in pediatrics Postoperative Nausea and Vomiting ( 2.1 ) Adult Dosage: a single 0.075 mg intravenous dose administered over 10 seconds immediately before the induction of anesthesia.

2.1 Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Age Dose* Infusion Time Adults 0 .

2 5 m g x 1 Infuse over 3 0 s e c o nd s beginning approx.

30 min before the start of chemo Pediatrics (1 month to less than 17 years) 2 0 m icr o g r a m s p er k il o g r a m (max 1.5 mg) x 1 Infuse over 1 5 m i nut es beginning approx.

30 min before the start of chemo *Note different dosing units in pediatrics Postoperative Nausea and Vomiting Dosage for Adults – a single 0.075 mg intravenous dose administered over 10 seconds immediately before the induction of anesthesia.

2.2 Instructions for I ntravenous Administration ALOXI is supplied ready for intravenous administration at a concentration of 0.05 mg/mL (50 mcg/ mL).

ALOXI should not be mixed with other drugs.

The infusion line should be flushed with normal saline before and after administration of ALOXI.

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