Drug Intercation

Clonazepam 0.25 MG Disintegrating Oral Tablet

Generic Name: CLONAZEPAM

Brand Name: Clonazepam

Substance Name(s):
CLONAZEPAM

WARNINGS

Risks from Concomitant Use With Opioids: Concomitant use of benzodiazepines, including clonazepam orally disintegrating tablets, and opioids may result in profound sedation, respiratory depression, coma, and death.

Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone.

If a decision is made to prescribe clonazepam orally disintegrating tablets concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when clonazepam orally disintegrating tablet is used with opioids (see PRECAUTIONS; Information for Patients and PRECAUTIONS: Drug Interactions ).

Abuse, Misuse, and Addiction: The use of benzodiazepines, including clonazepam orally disintegrating tablets, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death.

Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE: Abuse ) .

Before prescribing clonazepam orally disintegrating tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool).

Use of clonazepam orally disintegrating tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of clonazepam orally disintegrating tablets along with monitoring for signs and symptoms of abuse, misuse, and addiction.

Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug.

If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

Dependence and Withdrawal Reactions: To reduce the risk of withdrawal reactions, use a gradual taper to discontinue clonazepam orally disintegrating tablets or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION : Discontinuation or Dosage Reduction of CLONAZEPAM ORALLY DISINTEGRATING TABLETS ) .

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

Acute Withdrawal Reactions The continued use of benzodiazepines, including clonazepam orally disintegrating tablets, may lead to clinically significant physical dependence.

Abrupt discontinuation or rapid dosage reduction of clonazepam orally disintegrating tablets after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE: Dependence ) .

Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE : Dependence ).

Interference With Cognitive and Motor Performance: Since clonazepam orally disintegrating tablets produces CNS depression, patients receiving this drug should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery or driving a motor vehicle.

They should also be warned about the concomitant use of alcohol or other CNS-depressant drugs during clonazepam orally disintegrating tablets therapy [see PRECAUTIONS, Drug Interactions and Information for Patients ].

Suicidal Behavior and Ideation : Antiepileptic drugs (AEDs),including clonazepam orally disintegrating tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.

There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/ Incidence In Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing clonazepam orally disintegrating tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

Neonatal Sedation and Withdrawal Syndrome: Use of clonazepam orally disintegrating tablets late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see PRECAUTIONS: Pregnancy ).

Monitor neonates exposed to clonazepam orally disintegrating tablets during pregnancy or labor for signs of sedation and monitor neonates exposed to clonazepam orally disintegrating tablets during pregnancy for signs of withdrawal; manage these neonates accordingly.

DRUG INTERACTIONS

Drug Interactions: Effect of Concomitant Use of Benzodiazepines and Opioids: The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration.

Benzodiazepines interact at GABA A sites, and opioids interact primarily at mu receptors.

When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.

Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.

Effect of Clonazepam on the Pharmacokinetics of Other Drugs: Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital.

The effect of clonazepam on the metabolism of other drugs has not been investigated.

Effect of Other Drugs on the Pharmacokinetics of Clonazepam: Literature reports suggest that ranitidine, an agent that decreases stomach acidity, does not greatly alter clonazepam pharmacokinetics.

In a study in which the 2 mg clonazepam orally disintegrating tablet was administered with and without propantheline (an anticholinergic agent with multiple effects on the GI tract) to healthy volunteers, the AUC of clonazepam was 10% lower and the C max of clonazepam was 20% lower when the orally disintegrating tablet was given with propantheline compared to when it was given alone.

Fluoxetine does not affect the pharmacokinetics of clonazepam.

Cytochrome P-450 inducers, such as phenytoin, carbamazepine and phenobarbital, induce clonazepam metabolism, causing an approximately 30% decrease in plasma clonazepam levels.

Although clinical studies have not been performed, based on the involvement of the cytochrome P-450 3A family in clonazepam metabolism, inhibitors of this enzyme system, notably oral antifungal agents, should be used cautiously in patients receiving clonazepam.

Pharmacodynamic Interactions: The CNS-depressant action of the benzodiazepine class of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics, antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and by other anticonvulsant drugs.

OVERDOSAGE

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma.

In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia.

Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur.

In severe overdosage cases, patients may develop respiratory depression and coma.

Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Abuse, Misuse, and Addiction ).

Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance.

Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency.

The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy.

Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus).

If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage.

See the flumazenil injection Prescribing Information.

Consider contacting a poison center (1-800-222-1222) poisoncontrol.org, or a medical toxicologist for additional overdosage management recommendations.

DESCRIPTION

Clonazepam Orally Disintegrating Tablets, USP, a benzodiazepine, is available as an orally disintegrating tablet containing 0.125 mg, 0.25 mg, 0.5 mg, 1 mg or 2 mg clonazepam.

Each orally disintegrating tablet contains aspartame, crospovidone, magnesium stearate, mannitol, silicon dioxide, sorbitol, sodium lauryl sulfate, and talc.

Chemically, clonazepam is 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2 H -1,4-benzodiazepin-2-one.

It is a light yellow crystalline powder.

It has a molecular weight of 315.72 and the following structural formula: This is the structural formula.

HOW SUPPLIED

Clonazepam Orally Disintegrating Tablets USP, 0.125 mg are white, round, flat-faced, beveled edge tablets, debossed with “K5” and is available in a blister package of 60 (6 tablets/blister card, 10 blister cards/carton), NDC 49884-306-02.

Clonazepam Orally Disintegrating Tablets USP, 0.25 mg are white, round, flat-faced, beveled edge tablets, debossed with “K6” and is available in a blister package of 60 (6 tablets/blister card, 10 blister cards/carton), NDC 49884-307-02.

Clonazepam Orally Disintegrating Tablets USP, 0.5 mg are white, round, flat-faced, beveled edge tablets, debossed with “K7” and is available in a blister package of 60 (6 tablets/blister card, 10 blister cards/carton), NDC 49884-308-02.

Clonazepam Orally Disintegrating Tablets USP, 1 mg are white, round, flat-faced, beveled edge tablets, debossed with “K8” and is available in a blister package of 60 (6 tablets/blister card, 10 blister cards/carton), NDC 49884-309-02.

Clonazepam Orally Disintegrating Tablets USP, 2 mg are white, round, flat-faced, beveled edge tablets, debossed with “K9” and is available in a blister package of 60 (6 tablets/blister card, 10 blister cards/carton), NDC 49884-310-02.

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

Rx only Dist by: Par Pharmaceutical Cranbury, NJ 08512 U.S.A.

Revised:11/2022 This is 0.125 mg picture of pills.

This is 0.25 mg picture of pills.

This is 0.5 mg picture of pills.

This is 1 mg picture of pills.

This is 2 mg picture of pills.

GERIATRIC USE

Geriatric Use: Clinical studies of clonazepam orally disintegrating 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.

Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam orally disintegrating tablets elimination.

Metabolites of clonazepam orally disintegrating tablets are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function.

Because elderly patients are more likely to have decreased hepatic and/or renal function, care should be taken in dose selection, and it may be useful to assess hepatic and/or renal function at the time of dose selection.

Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of clonazepam orally disintegrating tablets and observed closely.

INDICATIONS AND USAGE

Seizure Disorders: Clonazepam orally disintegrating tablet is useful alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures.

In patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam orally disintegrating tablets may be useful.

In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often within 3 months of administration.

In some cases, dosage adjustment may reestablish efficacy.

Panic Disorder: Clonazepam orally disintegrating tablet is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-V.

Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.

The efficacy of clonazepam orally disintegrating tablets was established in two 6- to 9-week trials in panic disorder patients whose diagnoses corresponded to the DSM-lIlR category of panic disorder (see CLINICAL PHARMACOLOGY : Clinical Trials ).

Panic disorder (DSM-V) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

The effectiveness of clonazepam orally disintegrating tablets in long-term use, that is, for more than 9 weeks, has not been systematically studied in controlled clinical trials.

The physician who elects to use clonazepam orally disintegrating tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

PEDIATRIC USE

Pediatric Use: Because of the possibility that adverse effects on physical or mental development could become apparent only after many years, a benefit-risk consideration of the long-term use of clonazepam orally disintegrating tablet is important in pediatric patients being treated for seizure disorder [see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ].

Safety and effectiveness in pediatric patients with panic disorder below the age of 18 have not been established.

PREGNANCY

Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AED’s, such as clonazepam orally disintegrating tablets, during pregnancy.

Healthcare providers are encouraged to recommend that pregnant patients taking clonazepam orally disintegrating tablets enroll in the NAAED Pregnancy Registry by calling 1-888-233-2334, or online at http://www.aedpregnancyregistry.org/.

Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome , PRECATIONS: Clinical Considerations ).

Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data).

Administration of clonazepam to pregnant rabbits during the period of organogenesis resulted in developmental toxicity, including increased incidences of fetal malformations, at doses similar to or below therapeutic doses in patients (see Animal Data) .

Data for other benzodiazepines suggest the possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines at clinically relevant doses.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

In the U.S.

general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates.

Monitor neonates exposed to clonazepam orally disintegrating tablets during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.

Monitor neonates exposed to clonazepam orally disintegrating tablets during pregnancy for signs of withdrawal.

Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ) .

Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted.

In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data In three studies in which clonazepam orally disintegrating tablets was administered orally to pregnant rabbits at doses of 0.2, 1, 5 or 10 mg/kg/day (low dose approximately 0.2 times the maximum recommended human dose of 20 mg/day for seizure disorders and equivalent to the maximum dose of 4 mg/day for panic disorder, on a mg/m 2 basis) during the period of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused sternebrae and limb defects) was observed in a low, non-dose-related incidence in exposed litters from all dosage groups.

Reductions in maternal weight gain occurred at dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one study at a dosage of 10 mg/kg/day.

No adverse maternal or embryo-fetal effects were observed in mice and rats following administration during organogenesis of oral doses up to 15 mg/kg/day or 40 mg/kg/day, respectively (4 and 20 times the maximum recommended human dose of 20 mg/day for seizure disorders and 20 and 100 times the maximum dose of 4 mg/day for panic disorder, respectively, on a mg/m 2 basis).

NUSRING MOTHERS

Nursing Mothers: Risk Summary Clonazepam is excreted in human milk.

There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk.

There are no data on the effects of clonazepam on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for clonazepam orally disintegrating tablets and any potential adverse effects on the breastfed infant from clonazepam orally disintegrating tablets or from the underlying maternal condition.

Clinical Considerations Infants exposed to clonazepam through breast milk should be monitored for sedation, poor feeding and poor weight gain.

BOXED WARNING

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS).

The use of benzodiazepines, including clonazepam orally disintegrating tablets, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death.

Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes.

Before prescribing clonazepam orally disintegrating tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS) .

The continued use of benzodiazepines, including clonazepam orally disintegrating tablets, may lead to clinically significant physical dependence.

The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose .

Abrupt discontinuation or rapid dosage reduction of clonazepam orally disintegrating tablets after continued use may precipitate acute withdrawal reactions, which can be life-threatening.

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue clonazepam orally disintegrating tablets or reduce the dosage (see DOSAGE AND ADMINISTRATION and WARNINGS) .

INFORMATION FOR PATIENTS

Information for Patients: A clonazepam orally disintegrating tablets Medication Guide must be given to the patient each time clonazepam orally disintegrating tablets is dispensed, as required by law.

Patients should be instructed to take clonazepam orally disintegrating tablets only as prescribed.

Physicians are advised to discuss the following issues with patients for whom they prescribe clonazepam orally disintegrating tablets: Risks from Concomitant Use With Opioids Inform patients and caregivers that potentially fatal additive effects may occur if clonazepam is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider (see WARNINGS: Risks from Concomitant Use With Opioids and PRECAUTIONS: Drug Interactions ).

Abuse, Misuse, and Addiction: Inform patients that the use of clonazepam orally disintegrating tablets, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances .

Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug (see WARNINGS: Abuse, Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ) .

Withdrawal Reactions: Inform patients that the continued use of clonazepam orally disintegrating tablets may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of clonazepam orally disintegrating tablets may precipitate acute withdrawal reactions, which can be life-threatening.

Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months.

Instruct patients that discontinuation or dosage reduction of clonazepam orally disintegrating tablets may require a slow taper (see WARNINGS: Dependence and Withdrawal Reaction s and DRUG ABUSE AND DEPENDENCE ) .

Interference With Cognitive and Motor Performance : Because benzodiazepines have the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that clonazepam orally disintegrating tablets therapy does not affect them adversely.

Suicidal Thinking and Behavior: Patients, their caregivers, and families should be counseled that AEDs, including clonazepam orally disintegrating tablet, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

Pregnancy: Advise pregnant females that use of clonazepam orally disintegrating tablets late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS : Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy ).

Instruct patients to inform their healthcare provider if they are pregnant or intend to become pregnant.

Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant while taking clonazepam orally disintegrating tablets.

This registry is collecting information about the safety of antiepileptic drugs during pregnancy.

(see PRECAUTIONS: Pregnancy ).

Nursing: Instruct patients to inform their healthcare provider if they are breastfeeding or intend to breastfeed.

Instruct breastfeeding patients who take clonazepam orally disintegrating tablets to monitor their infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs (see PRECAUTIONS: Nursing Mothers ).

Concomitant Medication: Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.

Alcohol: Patients should be advised to avoid alcohol while taking clonazepam orally disintegrating tablets.

Phenylketonurics: Patients should be informed that clonazepam orally disintegrating tablets contain phenylalanine (a component of aspartame).

Each orally disintegrating tablet contains 0.56 mg phenylalanine.

DOSAGE AND ADMINISTRATION

Clonazepam is available as an orally disintegrating tablet.

The orally disintegrating tablet should be administered as follows: After opening the carton, peel back the foil on the blister.

Do not push tablet through foil.

Immediately upon opening the blister, using dry hands, remove the tablet and place it in the mouth.

Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or without water.

Seizure Disorders: Adults: The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses.

Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase.

Maintenance dosage must be individualized for each patient depending upon response.

Maximum recommended daily dose is 20 mg.

The use of multiple anticonvulsants may result in an increase of depressant adverse effects.

This should be considered before adding clonazepam orally disintegrating tablets to an existing anticonvulsant regimen.

Pediatric Patients: Clonazepam orally disintegrating tablets are administered orally.

In order to minimize drowsiness, the initial dose for infants and children (up to 10 years of age or 30 kg of body weight) should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in two or three divided doses.

Dosage should be increased by no more than 0.25 to 0.5 mg every third day until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weight has been reached, unless seizures are controlled or side effects preclude further increase.

Whenever possible, the daily dose should be divided into three equal doses.

If doses are not equally divided, the largest dose should be given before retiring.

Geriatric Patients: There is no clinical trial experience with clonazepam orally disintegrating tablets in seizure disorder patients 65 years of age and older.

In general, elderly patients should be started on low doses of clonazepam orally disintegrating tablets and observed closely [see PRECAUTIONS, Geriatric Us e ].

Panic Disorder: Adults: The initial dose for adults with panic disorder is 0.25 mg twice daily.

An increase to the target dose for most patients of 1 mg/day may be made after 3 days.

The recommended dose of 1 mg/day is based on the results from a fixed dose study in which the optimal effect was seen at 1 mg/day.

Higher doses of 2, 3 and 4 mg/day in that study were less effective than the 1 mg/day dose and were associated with more adverse effects.

Nevertheless, it is possible that some individual patients may benefit from doses of up to a maximum dose of 4 mg/day, and in those instances, the dose may be increased in increments of 0.125 to 0.25 mg bid every 3 days until panic disorder is controlled or until side effects make further increases undesired.

To reduce the inconvenience of somnolence, administration of one dose at bedtime may be desirable.

Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every 3 days, until the drug is completely withdrawn.

There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it.

Therefore, the physician who elects to use clonazepam orally disintegrating tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Pediatric Patients: There is no clinical trial experience with clonazepam orally disintegrating tablets in panic disorder patients under 18 years of age.

Geriatric Patients: There is no clinical trial experience with clonazepam orally disintegrating tablets in panic disorder patients 65 years of age and older.

In general, elderly patients should be started on low doses of clonazepam and observed closely [see PRECAUTIONS, Geriatric Use ].

Discontinuation or Dosage Reduction of clonazepam orally disintegrating tablets To reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use a gradual taper to discontinue clonazepam orally disintegrating tablets or reduce the dosage.

If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level.

Subsequently decrease the dosage more slowly (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE : Dependence ).

Remeron 45 MG Oral Tablet

DRUG INTERACTIONS

7 Table 5 includes clinically important drug interactions with REMERON/REMERONSolTab [see Clinical Pharmacology (12.3) ].

Table 5: Clinically Important Drug Interactions with REMERON/REMERONSolTab Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of serotonergic drugs, including REMERON/REMERONSolTab, and MAOIs increases the risk of serotonin syndrome.

Intervention REMERON/REMERONSolTab is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.4) , Contraindications (4) , Warnings and Precautions (5.3) ].

Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with REMERON/REMERONSolTab increases the risk of serotonin syndrome.

Intervention Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases.

If serotonin syndrome occurs, consider discontinuation of REMERON/REMERONSolTab and/or concomitant serotonergic drugs [see Warnings and Precautions (5.3) ].

Examples SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, amphetamines, St.

John’s Wort, tramadol, tryptophan, buspirone Strong CYP3A Inducers Clinical Impact The concomitant use of strong CYP3A inducers with REMERON/REMERONSolTab decreases the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3) ] .

Intervention Increase the dose of REMERON/REMERONSolTab if needed with concomitant CYP3A inducer use.

Conversely, a decrease in dosage of REMERON/REMERONSolTab may be needed if the CYP3A inducer is discontinued [see Dosage and Administration (2.5) ].

Examples phenytoin, carbamazepine, rifampin Strong CYP3A Inhibitors Clinical Impact The concomitant use of strong CYP3A inhibitors with REMERON/REMERONSolTab may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3) ] .

Intervention Decrease the dose of REMERON/REMERONSolTab if needed with concomitant strong CYP3A inhibitor use.

Conversely, an increase in dosage of REMERON/REMERONSolTab may be needed if the CYP3A inhibitor is discontinued [see Dosage and Administration (2.5) ].

Examples itraconazole, ritonavir, nefazodone Cimetidine Clinical Impact The concomitant use of cimetidine, a CYP1A2, CYP2D6, and CYP3A inhibitor, with REMERON/REMERONSolTab may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3) ].

Intervention Decrease the dose of REMERON/REMERONSolTab if needed with concomitant cimetidine use.

Conversely, an increase in dosage of REMERON/REMERONSolTab may be needed if cimetidine is discontinued [see Dosage and Administration (2.5) ] .

Benzodiazepines and Alcohol Clinical Impact The concomitant use of benzodiazepines or alcohol with REMERON/REMERONSolTab increases the impairment of cognitive and motor skills produced by REMERON/REMERONSolTab alone.

Intervention Avoid concomitant use of benzodiazepines and alcohol with REMERON/REMERONSolTab [see Warnings and Precautions (5.7) , Clinical Pharmacology (12.3) ] ] .

Examples diazepam, alprazolam, alcohol Drugs that Prolong QTc Interval Clinical Impact The concomitant use of other drugs which prolong the QTc interval with REMERON/REMERONSolTab, increase the risk of QT prolongation and/or ventricular arrhythmias (e.g., Torsades de Pointes).

Intervention Use caution when using REMERON/REMERONSolTab concomitantly with drugs that prolong the QTc interval [see Warnings and Precautions (5.5) , Clinical Pharmacology (12.3) ].

Warfarin Clinical Impact The concomitant use of warfarin with REMERON/REMERONSolTab may result in an increase in INR [see Clinical Pharmacology (12.3) ] .

Intervention Monitor INR during concomitant use of warfarin with REMERON/REMERONSolTab.

Strong CYP3A inducers: Dosage increase may be needed for REMERON/REMERONSolTab with concomitant use of strong CYP3A inducers.

( 2.5 , 7 ) Strong CYP3A inhibitors : Dosage decrease may be needed when REMERON/REMERONSolTab is coadministered with strong CYP3A inhibitors.

( 2.5 , 7 ) Cimetidine: Dosage decrease may be needed when REMERON/REMERONSolTab is coadministered with cimetidine.

( 2.5 , 7 ) Warfarin : Monitor INR during concomitant use.

( 7 )

OVERDOSAGE

10 Human Experience In premarketing clinical studies, there were reports of REMERON overdose alone or in combination with other pharmacological agents.

Signs and symptoms reported in association with overdose included disorientation, drowsiness, impaired memory, and tachycardia.

Based on postmarketing reports, serious outcomes (including fatalities) may occur at dosages higher than the recommended doses, especially with mixed overdoses.

In these cases, QT prolongation and Torsades de Pointes have also been reported [see Warnings and Precautions (5.5) , Adverse Reactions (6.2) , and Drug Interactions (7) ].

Overdose Management No specific antidotes for mirtazapine are known.

Contact Poison Control (1-800-222-1222) for the latest recommendations.

DESCRIPTION

11 REMERON and REMERONSolTab contain mirtazapine.

Mirtazapine has a tetracyclic chemical structure and belongs to the piperazino-azepine group of compounds.

It is designated 1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c][2] benzazepine and has the empirical formula of C 17 H 19 N 3 .

Its molecular weight is 265.35.

The structural formula is the following and it is the racemic mixture: Mirtazapine is a white to creamy white crystalline powder which is practically insoluble in water.

REMERON is available for oral administration as scored film-coated tablets containing 15 or 30 mg of mirtazapine Each tablet contains the following inactive ingredients: colloidal silicon dioxide anhydrous, corn starch, ferric oxide (yellow), hydroxypropyl cellulose, hypromellose, magnesium stearate, lactose monohydrate, polyethylene glycol 8000, and titanium dioxide.

The 30 mg tablets also contain ferric oxide (red).

REMERONSolTab is available for oral administration as an orally disintegrating tablet containing 15, 30, or 45 mg of mirtazapine.

REMERONSolTab also contains the following inactive ingredients: aspartame, citric acid anhydrous fine granular, crospovidone, hypromellose, magnesium stearate, mannitol, granular mannitol 2080, microcrystalline cellulose, natural and artificial orange flavor, polymethacrylate (Eudragit E100), povidone, sodium bicarbonate, and sugar spheres (composed of starch and sucrose).

Chemical Structure

CLINICAL STUDIES

14 The efficacy of REMERON as a treatment for major depressive disorder was established in 4 placebo-controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major depressive disorder.

Patients were titrated with REMERON from a dose range of 5 mg to 35 mg/day.

The mean mirtazapine dose for patients who completed these 4 studies ranged from 21 to 32 mg/day.

Overall, these studies demonstrated REMERON to be superior to placebo on at least 3 of the following 4 measures: 21-Item Hamilton Depression Rating Scale (HDRS) total score; HDRS Depressed Mood Item; CGI Severity score; and Montgomery and Asberg Depression Rating Scale (MADRS).

Superiority of REMERON over placebo was also found for certain factors of the HDRS, including anxiety/somatization factor and sleep disturbance factor.

Examination of age and gender subsets of the population did not reveal any differential responsiveness on the basis of these subgroupings.

In a longer-term study, patients meeting (DSM-IV) criteria for major depressive disorder who had responded during an initial 8 to 12 weeks of acute treatment on REMERON were randomized to continuation of REMERON or placebo for up to 40 weeks of observation for relapse.

Response during the open phase was defined as having achieved a HAM-D 17 total score of ≤8 and a CGI-Improvement score of 1 or 2 at 2 consecutive visits beginning with week 6 of the 8 to 12 weeks in the open-label phase of the study.

Relapse during the double-blind phase was determined by the individual investigators.

Patients receiving continued REMERON treatment experienced significantly lower relapse rates over the subsequent 40 weeks compared to those receiving placebo.

This pattern was demonstrated in both male and female patients.

HOW SUPPLIED

16 /STORAGE AND HANDLING REMERON tablets are supplied as: Tablet Strength Tablet Color/Shape Tablet Markings Package Configuration NDC Code 15 mg Yellow, oval tablet Scored with “Organon” debossed on one side and ” T 3 Z ” on other side, on both sides of score line Bottle / 30 count 0052-0105-30 15 mg Yellow, oval tablet Scored with “MSD” debossed on one side and ” T 3 Z ” on other side, on both sides of score line Bottle / 30 count 0052-4364-01 30 mg Red-brown, oval tablet Scored with “Organon” debossed on one side and ” T 5 Z ” on other side, on both sides of score line Bottle / 30 count 0052-0107-30 30 mg Red-brown, oval tablet Scored with “MSD” debossed on one side and ” T 5 Z ” on other side, on both sides of score line Bottle / 30 count 0052-4365-01 Storage 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) [see USP Controlled Room Temperature].

Protect from light and moisture.

REMERONSolTab orally disintegrating tablets are supplied as: Tablet Strength Tablet Color/Shape Tablet Markings Package Configuration NDC Code 15 mg White, round tablet ” T 1 Z ” debossed on one side.

Box of 5 × 6-unit dose blister packs/ 30 count 0052-0106-30 30 mg White, round tablet ” T 2 Z ” debossed on one side.

Box of 5 × 6-unit dose blister packs/30 count 0052-0108-30 45 mg White, round tablet ” T 4 Z ” debossed on one side Box of 5 × 6-unit dose blister packs/30 count 0052-0110-30 Storage 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) [see USP Controlled Room Temperature].

Protect from light and moisture.

Use immediately upon opening individual tablet blister.

GERIATRIC USE

8.5 Geriatric Use Approximately 190 patients ≥65 years of age participated in clinical studies with REMERON.

REMERON/REMERONSolTab is known to be substantially excreted by the kidney (75%), and the risk of decreased clearance of this drug is greater in patients with impaired renal function.

Pharmacokinetic studies revealed a decreased clearance of mirtazapine in the elderly [see Clinical Pharmacology (12.3) ] .

Sedating drugs, including REMERON/REMERONSolTab, may cause confusion and over-sedation in the elderly.

Elderly patients may be at greater risk of developing hyponatremia.

Caution is indicated when administering REMERON/REMERONSolTab to elderly patients [see Warnings and Precautions (5.11) , (5.14) and Clinical Pharmacology (12.3) ] .

In general, dose selection for an elderly patient should be conservative, 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.

DOSAGE FORMS AND STRENGTHS

3 REMERON is supplied as: 15 mg tablets: Oval, scored, yellow, with “Organon” debossed on one side and ” T 3 Z ” on the other side, on both sides of the score line 15 mg tablets: Oval, scored, yellow, with “MSD” debossed on one side and ” T 3 Z ” on the other side, on both sides of the score line 30 mg tablets: Oval, scored, red-brown, with “Organon” debossed on one side and ” T 5 Z ” on the other side, on both sides of the score line 30 mg tablets: Oval, scored, red-brown, with “MSD” debossed on one side and ” T 5 Z ” on the other side, on both sides of the score line REMERONSolTab is supplied as: 15 mg orally disintegrating tablets: Round, white, with ” T 1 Z ” debossed on one side 30 mg orally disintegrating tablets: Round, white, with ” T 2 Z ” debossed on one side 45 mg orally disintegrating tablets: Round, white, with ” T 4 Z ” debossed on one side Tablets : 15 mg scored and 30 mg scored.

( 3 ) Orally disintegrating tablets : 15 mg, 30 mg, and 45 mg.

( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism of action of mirtazapine for the treatment of major depressive disorder, is unclear.

However, its efficacy could be mediated through its activity as an antagonist at central presynaptic α 2 -adrenergic inhibitory autoreceptors and heteroreceptors and enhancing central noradrenergic and serotonergic activity.

INDICATIONS AND USAGE

1 REMERON/REMERONSolTab are indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies (14) ] .

REMERON/REMERONSolTab is indicated for the treatment of major depressive disorder (MDD) in adults.

( 1 )

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of REMERON/REMERONSolTab have not been established in pediatric patients with MDD.

Two placebo-controlled trials in 258 pediatric patients with MDD have been conducted with REMERON, and the data were insufficient to establish the safety and effectiveness of REMERON/REMERONSolTab in pediatric patients with MDD.

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning and Warnings and Precautions (5.1) ] .

In an 8-week-long clinical trial in pediatric patients receiving doses between 15 to 45 mg per day, 49% of REMERON-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients.

The mean increase in weight was 4 kg (2 kg SD) for REMERON-treated patients versus 1 kg (2 kg SD) for placebo-treated patients [see Warnings and Precautions (5.6) ] .

PREGNANCY

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.

Risk Summary Prolonged experience with mirtazapine in pregnant women, based on published observational studies and postmarketing reports, has not reliably identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

There are risks associated with untreated depression in pregnancy (see Clinical Considerations ).

In animal reproduction studies, oral administration of mirtazapine to pregnant rats and rabbits during the period of organogenesis revealed no evidence of teratogenic effects up to 20 and 17 times the maximum recommended human dose (MRHD) of 45 mg, respectively, based on mg/m 2 body surface area.

However, in rats, there was an increase in postimplantation loss at 20 times the MRHD based on mg/m 2 body surface area.

Oral administration of mirtazapine to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths and a decrease in pup birth weights at doses 20 times the MRHD based on mg/m 2 body surface area (see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants.

This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy.

Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

Data Animal Data Mirtazapine was administered orally to pregnant rats and rabbits during the period of organogenesis at doses of 2.5, 15, and 100 mg/kg/day and 2.5, 10, and 40 mg/kg/day, respectively, which are up to 20 and 17 times the maximum recommended human dose (MRHD) of 45 mg based on mg/m 2 body surface area, respectively.

No evidence of teratogenic effects was observed.

However, in rats, there was an increase in postimplantation loss in dams treated with mirtazapine at 100 mg/kg/day which is 20 times the MRHD based on mg/m 2 body surface area.

Oral administration of mirtazapine at doses of 2.5, 15, and 100 mg/kg/day to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights at 20 times the MRHD based on mg/m 2 body surface area.

The cause of these deaths is not known.

The no effect dose level is 3 times the MRHD based on mg/m 2 body surface area.

BOXED WARNING

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies.

Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1) ] .

REMERON/REMERONSolTab is not approved for use in pediatric patients [see Use in Specific Populations (8.4) ].

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning.

Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants.

Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors.

REMERON/REMERONSolTab is not approved for use in pediatric patients.

( 5.1 , 8.4 )

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Agranulocytosis : If sore throat, fever, stomatitis or signs of infection occur, along with a low white blood cell count, treatment with REMERON/REMERONSolTab should be discontinued and the patient should be closely monitored.

( 5.2 ) Serotonin Syndrome : Increased risk when co-administered with other serotonergic drugs (e.g., SSRI, SNRI, triptans), but also when taken alone.

If it occurs, discontinue REMERON/REMERONSolTab and initiate supportive treatment.

( 2.4 , 4 , 5.3 , 7 ) Angle-Closure Glaucoma : Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.

( 5.4 ) QT Prolongation : Use REMERON/REMERONSolTab with caution in patients with risk factors for QT prolongation.

( 5.5 , 7 ) Increased Appetite/Weight Gain : REMERON/REMERONSolTab has been associated with increased appetite and weight gain.

( 5.6 ) Somnolence : May impair judgment, thinking and/or motor skills.

Use with caution when engaging in activities requiring alertness, such as driving or operating machinery.

( 5.7 , 7 ) Activation of Mania/Hypomania : Screen patients for bipolar disorder prior to initiating treatment.

( 2.3 , 5.8 ) Seizures : Use with caution in patients with a seizure disorder.

( 5.9 ) Elevated Cholesterol/Triglycerides : Has been reported with REMERON use.

( 5.10 ) Hyponatremia : May occur as a result of treatment with serotonergic antidepressants, including REMERON/REMERONSolTab.

( 5.11 ) Transaminase Elevations : Clinically significant elevations have occurred.

Use with caution in patients with impaired hepatic function.

( 5.12 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients.

There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.

There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD.

The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.

Table 1: Risk Differences of the Number of Patients with Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18–24 years old 5 additional patients Decreases Compared to Placebo 25–64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication of clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes.

Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider.

Consider changing the therapeutic regimen, including possibly discontinuing REMERON/REMERONSolTab, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Agranulocytosis In premarketing clinical trials, 2 (1 with Sjögren’s Syndrome) out of 2796 patients treated with REMERON developed agranulocytosis [absolute neutrophil count (ANC) <500/mm 3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC <500/mm 3 without any associated symptoms).

For these 3 patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively.

All 3 patients recovered after REMERON was stopped.

If a patient develops a sore throat, fever, stomatitis, or other signs of infection, along with a low white blood cell (WBC) count, treatment with REMERON/REMERONSolTab should be discontinued and the patient should be closely monitored.

5.3 Serotonin Syndrome Serotonergic antidepressants, including REMERON/REMERONSolTab, can precipitate serotonin syndrome, a potentially life-threatening condition.

The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.

John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4) , Drug Interactions (7) ] .

Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and symptoms may include 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, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of REMERON/REMERONSolTab with MAOIs is contraindicated.

In addition, do not initiate REMERON/REMERONSolTab in a patient being treated with MAOIs such as linezolid or intravenous methylene blue.

No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection).

If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking REMERON/REMERONSolTab, discontinue REMERON/REMERONSolTab before initiating treatment with the MAOI [see Contraindications (4) , Drug Interactions (7) ] .

Monitor all patients taking REMERON/REMERONSolTab for the emergence of serotonin syndrome.

Discontinue treatment with REMERON/REMERONSolTab and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment.

If concomitant use of REMERON/REMERONSolTab with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.4 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs, including REMERON/REMERONSolTab, may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.5 QT Prolongation and Torsades de Pointes The effect of REMERON (mirtazapine) on QTc interval was assessed in a clinical randomized trial with placebo and positive (moxifloxacin) controls involving 54 healthy volunteers using exposure response analysis.

This trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval.

However, the degree of QT prolongation observed with both 45 mg and 75 mg (1.67 times the maximum recommended daily dose) doses of mirtazapine was not at a level generally considered to be clinically meaningful.

During postmarketing use of mirtazapine, cases of QT prolongation, Torsades de Pointes, ventricular tachycardia, and sudden death, have been reported [see Adverse Reactions (6.1 , 6.2) ] .

The majority of reports occurred in association with overdose or in patients with other risk factors for QT prolongation, including concomitant use of QTc-prolonging medicines [see Drug Interactions (7) and Overdosage (10) ] .

Exercise caution when REMERON/REMERONSolTab is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other drugs thought to prolong the QTc interval.

5.6 Increased Appetite and Weight Gain In U.S.

controlled clinical studies, appetite increase was reported in 17% of patients treated with REMERON, compared to 2% for placebo.

In these same trials, weight gain of ≥7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo.

In a pool of premarketing U.S.

clinical studies, including many patients for long-term, open-label treatment, 8% of patients receiving REMERON discontinued for weight gain.

In an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of REMERON-treated pediatric patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients.

The safety and effectiveness of REMERON/REMERONSolTab in pediatric patients with MDD have not been established [see Use in Specific Populations (8.4) ] .

5.7 Somnolence In U.S.

controlled studies, somnolence was reported in 54% of patients treated with REMERON, compared to 18% for placebo.

In these studies, somnolence resulted in discontinuation for 10.4% of REMERON-treated patients, compared to 2.2% for placebo.

It is unclear whether tolerance develops to the somnolent effects of REMERON/REMERONSolTab.

Because of the potentially significant effects of REMERON/REMERONSolTab on impairment of performance, caution patients about engaging in activities that require alertness, including operating hazardous machinery and motor vehicles, until they are reasonably certain that REMERON/REMERONSolTab does not affect them adversely.

The concomitant use of benzodiazepines and alcohol with REMERON/REMERONSolTab should be avoided [see Drug Interactions (7) ] .

5.8 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with REMERON/REMERONSolTab or another antidepressant may precipitate a mixed/manic episode.

In controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.2% of patients treated with REMERON.

Prior to initiating treatment with REMERON/REMERONSolTab, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

5.9 Seizures REMERON/REMERONSolTab has not been systematically evaluated in patients with seizure disorders.

In premarketing clinical trials, 1 seizure was reported among the 2796 U.S.

and non-U.S.

patients treated with REMERON.

REMERON/REMERONSolTab should be prescribed with caution in patients with a seizure disorder.

5.10 Elevated Cholesterol and Triglycerides In U.S.

controlled studies, nonfasting cholesterol increases to ≥20% above the upper limits of normal were observed in 15% of patients treated with REMERON, compared to 7% for placebo.

In these same studies, nonfasting triglyceride increases to ≥500 mg/dL were observed in 6% of patients treated with REMERON, compared to 3% for placebo.

5.11 Hyponatremia Hyponatremia may occur as a result of treatment with serotonergic antidepressants, including REMERON/REMERONSolTab.

Cases with serum sodium lower than 110 mmol/L have been reported.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.

Signs and symptoms associated with more severe or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue REMERON/REMERONSolTab and institute appropriate medical intervention.

Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia [see Use in Specific Populations (8.5) ] .

5.12 Transaminase Elevations Clinically significant ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients treated with REMERON in a pool of short-term, U.S.

controlled trials, compared to 0.3% (1/328) of placebo patients.

While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued REMERON treatment.

REMERON/REMERONSolTab should be used with caution in patients with impaired hepatic function [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] .

5.13 Discontinuation Syndrome There have been reports of adverse reactions upon the discontinuation of REMERON/REMERONSolTab (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesia and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting, and sweating, or other symptoms which may be of clinical significance.

A gradual reduction in the dosage, rather than an abrupt cessation, is recommended [see Dosage and Administration (2.6) ].

5.14 Use in Patients with Concomitant Illness REMERON/REMERONSolTab has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease.

REMERON was associated with significant orthostatic hypotension in early clinical pharmacology trials with normal volunteers.

Orthostatic hypotension was infrequently observed in clinical trials with depressed patients [see Adverse Reactions (6.1) ] .

REMERON/REMERONSolTab should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication).

5.15 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU).

REMERONSolTab contains phenylalanine, a component of aspartame.

REMERONSolTab contains the following amount of phenylalanine: 2.6 mg in 15 mg orally disintegrating tablet, 5.2 mg in 30 mg orally disintegrating tablet, and 7.8 mg in 45 mg orally disintegrating tablet.

Before prescribing REMERONSolTab to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including REMERONSolTab.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1) ].

Agranulocytosis Advise patients to contact their physician if they experience fever, chills, sore throat, mucous membrane ulceration, flu-like complaints, or other symptoms that might suggest infection [see Warnings and Precautions (5.2) ].

Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of REMERON/REMERONSolTab with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St.

John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid).

Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Dosage and Administration (2.4) , Contraindications (4) , Warnings and Precautions (5.3) , Drug Interactions (7) ].

QT Prolongation and Torsades de Pointes Inform patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations [see Warnings and Precautions (5.5) , Drug Interactions (7) , Overdosage (10) ].

Advise patients to inform physicians that they are taking REMERON/REMERONSolTab before any new drug is taken.

Somnolence Advise patients that REMERON/REMERONSolTab may impair judgment, thinking, and particularly, motor skills, because of its prominent sedative effect.

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that REMERON/REMERONSolTab therapy does not adversely affect their ability to engage in such activities.

[see Warnings and Precautions (5.7) ].

Alcohol Advise patients to avoid alcohol while taking REMERON/REMERONSolTab [see Warnings and Precautions (5.7) , Drug Interactions (7) ].

Activation of Mania/Hypomania Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.8) ] .

Discontinuation Syndrome Advise patients not to abruptly discontinue REMERON/REMERONSolTab and to discuss any tapering regimen with their healthcare provider.

Adverse reactions can occur when REMERON/REMERONSolTab is discontinued [see Dosage and Administration (2.6) , Warnings and Precautions (5.13) ].

Allergic Reactions Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [see Contraindications (4) , Adverse Reactions (6.2) ] .

Pregnancy Advise patients to notify their physician if they become pregnant or intend to become pregnant during REMERON/REMERONSolTab therapy.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to REMERON/REMERONSolTab during pregnancy [see Use in Specific Populations (8.1) ] .

Lactation Advise patients to notify their physician if they are breastfeeding an infant [see Use in Specific Populations (8.2) ].

Angle-Closure Glaucoma Patients should be advised that taking REMERON 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 [see Warnings and Precautions (5.4) .] Patients with Phenylketonuria Inform patients with phenylketonuria that REMERONSolTab contains phenylalanine [see Warnings and Precautions (5.15) ].

DOSAGE AND ADMINISTRATION

2 Starting dose: 15-mg once daily; may increase up to maximum recommended dose of 45 mg once daily.

( 2.1 ) Administer orally once daily, preferably in the evening prior to sleep.

( 2.1 ) Administer REMERONSolTab immediately after removal from blister pack.

( 2.2 ) Reduce dose gradually when discontinuing REMERON/REMERONSolTab.

( 2.6 , 5.13 ) 2.1 Recommended Dosage The recommended starting dose of REMERON/REMERONSolTab is 15 mg once daily, administered orally, preferably in the evening prior to sleep.

If patients do not have an adequate response to the initial 15 mg dose, increase the dose up to a maximum of 45 mg per day.

Dose changes should not be made in intervals of less than 1 to 2 weeks to allow sufficient time for evaluation of response to a given dose [see Clinical Pharmacology (12.3) ] .

2.2 Administration of REMERONSolTab The tablet should remain in the blister pack until the patient is ready to take it.

The patient or caregiver should use dry hands to open the blister.

As soon as the blister is opened, the tablet should be removed and placed on the patient’s tongue.

Use REMERONSolTab immediately after removal from its blister; once removed, it cannot be stored.

The whole tablet should be placed on the tongue and allowed to disintegrate without chewing or crushing.

Do not attempt to split the tablet.

The tablet will disintegrate in saliva so that it can be swallowed.

2.3 Screen for Bipolar Disorder Prior to Starting REMERON/REMERONSolTab Prior to initiating treatment with REMERON/REMERONSolTab or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.8) ].

2.4 Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of REMERON/REMERONSolTab.

In addition, at least 14 days must elapse after stopping REMERON/REMERONSolTab before starting an MAOI antidepressant [see Contraindications (4) and Warnings and Precautions (5.3) ] .

2.5 Dosage Modifications Due to Drug Interactions Strong CYP3A Inducers An increase in dosage of REMERON/REMERONSolTab may be needed with concomitant strong CYP3A inducer (e.g., carbamazepine, phenytoin, rifampin) use.

Conversely, a decrease in dosage of REMERON/REMERONSolTab may be needed if the CYP3A inducer is discontinued [see Drug Interactions (7) ].

Strong CYP3A Inhibitors A decrease in dosage of REMERON/REMERONSolTab may be needed with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin).

Conversely, an increase in dosage of REMERON/REMERONSolTab may be needed if the CYP3A4 inhibitor is discontinued [see Drug Interactions (7) ].

Cimetidine A decrease in dosage of REMERON/REMERONSolTab may be needed with concomitant use of cimetidine.

Conversely, an increase in dosage of REMERON/REMERONSolTab may be needed if cimetidine is discontinued [see Drug Interactions (7) ].

2.6 Discontinuation of REMERON/REMERONSolTab Treatment Adverse reactions may occur upon discontinuation or dose reduction of REMERON/REMERONSolTab [see Warnings and Precautions (5.13) ] .

Gradually reduce the dosage of REMERON/REMERONSolTab rather than stopping abruptly whenever possible.

Calcitriol 0.00025 MG Oral Capsule

WARNINGS

Overdosage of any form of vitamin D is dangerous (see OVERDOSAGE ).

Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention.

Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis and other soft-tissue calcification.

The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg 2 /dL 2 .

Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.

Calcitriol is the most potent metabolite of vitamin D available.

The administration of calcitriol to patients in excess of their daily requirements can cause hypercalcemia, hypercalciuria, and hyperphosphatemia.

Therefore, pharmacologic doses of vitamin D and its derivatives should be withheld during calcitriol treatment to avoid possible additive effects and hypercalcemia.

If treatment is switched from ergocalciferol (vitamin D 2 ) to calcitriol, it may take several months for the ergocalciferol level in the blood to return to the baseline value (see OVERDOSAGE ).

Calcitriol increases inorganic phosphate levels in serum.

While this is desirable in patients with hypophosphatemia, caution is called for in patients with renal failure because of the danger of ectopic calcification.

A non-aluminum phosphate-binding compound and a low-phosphate diet should be used to control serum phosphorus levels in patients undergoing dialysis.

Magnesium-containing preparations (eg, antacids) and calcitriol should not be used concomitantly in patients on chronic renal dialysis because such use may lead to the development of hypermagnesemia.

Studies in dogs and rats given calcitriol for up to 26 weeks have shown that small increases of calcitriol above endogenous levels can lead to abnormalities of calcium metabolism with the potential for calcification of many tissues in the body.

DRUG INTERACTIONS

Drug Interactions Cholestyramine Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; as such it may impair intestinal absorption of calcitriol (see WARNINGS and PRECAUTIONS : General ).

Phenytoin/Phenobarbital The coadministration of phenytoin or phenobarbital will not affect plasma concentrations of calcitriol, but may reduce endogenous plasma levels of 25(OH)D 3 by accelerating metabolism.

Since blood level of calcitriol will be reduced, higher doses of calcitriol may be necessary if these drugs are administered simultaneously.

Thiazides Thiazides are known to induce hypercalcemia by the reduction of calcium excretion in urine.

Some reports have shown that the concomitant administration of thiazides with calcitriol causes hypercalcemia.

Therefore, precaution should be taken when coadministration is necessary.

Digitalis Calcitriol dosage must be determined with care in patients undergoing treatment with digitalis, as hypercalcemia in such patients may precipitate cardiac arrhythmias (see PRECAUTIONS : General ).

Ketoconazole Ketoconazole may inhibit both synthetic and catabolic enzymes of calcitriol.

Reductions in serum endogenous calcitriol concentrations have been observed following the administration of 300 mg/day to 1200 mg/day ketoconazole for a week to healthy men.

However, in vivo drug interaction studies of ketoconazole with calcitriol have not been investigated.

Corticosteroids A relationship of functional antagonism exists between vitamin D analogues, which promote calcium absorption, and corticosteroids, which inhibit calcium absorption.

Phosphate-Binding Agents Since calcitriol also has an effect on phosphate transport in the intestine, kidneys and bones, the dosage of phosphate-binding agents must be adjusted in accordance with the serum phosphate concentration.

Vitamin D Since calcitriol is the most potent active metabolite of vitamin D3, pharmacological doses of vitamin D and its derivatives should be withheld during treatment with calcitriol to avoid possible additive effects and hypercalcemia (see WARNINGS ).

Calcium Supplements: Uncontrolled intake of additional calcium-containing preparations should be avoided (see PRECAUTIONS : General ).

Magnesium Magnesium-containing preparations (eg, antacids) may cause hypermagnesemia and should therefore not be taken during therapy with calcitriol by patients on chronic renal dialysis.

Carcinogenesis, Mutagenesis and Impairment of Fertility Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of calcitriol.

Calcitriol is not mutagenic in vitro in the Ames Test, nor is it genotoxic in vivo in the Mouse Micronucleus Test.

No significant effects of calcitriol on fertility and/or general reproductive performances were observed in a Segment I study in rats at doses of up to 0.3 mcg/kg (approximately 3 times the maximum recommended dose based on body surface area).

OVERDOSAGE

Administration of calcitriol to patients in excess of their daily requirements can cause hypercalcemia, hypercalciuria and hyperphosphatemia.

Since calcitriol is a derivative of vitamin D, the signs and symptoms of overdose are the same as for an overdose of vitamin D (see ADVERSE REACTIONS ).

High intake of calcium and phosphate concomitant with calcitriol may lead to similar abnormalities.

The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg2/dL2.

High levels of calcium in the dialysate bath may contribute to the hypercalcemia (see WARNINGS ).

Treatment of Hypercalcemia and Overdosage in Dialysis Patients and Hypoparathyroidism Patients General treatment of hypercalcemia (greater than 1 mg/dL above the upper limit of the normal range) consists of immediate discontinuation of calcitriol therapy, institution of a low-calcium diet and withdrawal of calcium supplements.

Serum calcium levels should be determined daily until normocalcemia ensues.

Hypercalcemia frequently resolves in 2 to 7 days.

When serum calcium levels have returned to within normal limits, calcitriol therapy may be reinstituted at a dose of 0.25 mcg/day less than prior therapy.

Serum calcium levels should be obtained at least twice weekly after all dosage changes and subsequent dosage titration.

In dialysis patients, persistent or markedly elevated serum calcium levels may be corrected by dialysis against a calcium-free dialysate.

Treatment of Hypercalcemia and Overdosage in Predialysis Patients If hypercalcemia ensues (greater than 1 mg/dL above the upper limit of the normal range), adjust dosage to achieve normocalcemia by reducing calcitriol therapy from 0.5 mcg to 0.25 mcg daily.

If the patient is receiving a therapy of 0.25 mcg daily, discontinue calcitriol until patient becomes normocalcemic.

Calcium supplements should also be reduced or discontinued.

Serum calcium levels should be determined 1 week after withdrawal of calcium supplements.

If serum calcium levels have returned to normal, calcitriol therapy may be reinstituted at a dosage of 0.25 mcg/day if previous therapy was at a dosage of 0.5 mcg/day.

If calcitriol therapy was previously administered at a dosage of 0.25 mcg/day, calcitriol therapy may be reinstituted at a dosage of 0.25 mcg every other day.

If hypercalcemia is persistent at the reduced dosage, serum PTH should be measured.

If serum PTH is normal, discontinue calcitriol therapy and monitor patient in 3 months’ time.

Treatment of Hyperphosphatemia in Predialysis Patients If serum phosphorus levels exceed 5 mg/dL to 5.5 mg/dL, a calcium-containing phosphate-binding agent (ie, calcium carbonate or calcium acetate) should be taken with meals.

Serum phosphorus levels should be determined as described earlier (see PRECAUTIONS : Laboratory Tests ).

Aluminum-containing gels should be used with caution as phosphate-binding agents because of the risk of slow aluminum accumulation.

Treatment of Accidental Overdosage of Calcitriol The treatment of acute accidental overdosage of calcitriol should consist of general supportive measures.

If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption.

If the drug has passed through the stomach, the administration of mineral oil may promote its fecal elimination.

Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion and assessment of eIectrocardiographic abnormalities due to hypercalcemia should be obtained.

Such monitoring is critical in patients receiving digitalis.

Discontinuation of supplemental calcium and a low-calcium diet are also indicated in accidental overdosage.

Due to the relatively short duration of the pharmacological action of calcitriol, further measures are probably unnecessary.

Should, however, persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives which may be considered, depending on the patient’s underlying condition.

These include the use of drugs such as phosphates and corticosteroids as well as measures to induce an appropriate forced diuresis.

The use of peritoneal dialysis against a calcium-free dialysate has also been reported.

DESCRIPTION

Calcitriol is a synthetic vitamin D analog which is active in the regulation of the absorption of calcium from the gastrointestinal tract and its utilization in the body.

Cacitriol is available as capsules containing 0.25 mcg.

Calcitriol Capsules contain butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) as antioxidants.

The capsules contain a fractionated triglyceride of coconut oil.

Gelatin capsule shells contain gelatin, glycerin (anhydrous), and titanium dioxide, with the following dyes: FD&C Yellow No.

5 and FD&C Yellow No.

In addition to the ingredients listed above, each tablet contains Opacode (Black) monogramming ink, Opacode (Black) contains ammonium hydroxide, iron oxide black, isopropyl alcohol, macrogol, polyvinyl acetate phthalate, propylene glycol, purified water, and SDA 35A alcohol.

Calcitriol is a white, crystalline compound which occurs naturally in humans.

It has a calculated molecular weight of 416.65 and is soluble in organic solvents but relatively insoluble in water.

Chemically, calcitriol is 9,10-seco(5Z,7E)-5,7,10(19)-cholestatriene-1α, 3β, 25-triol and has the following structural formula: The other names frequently used for calcitriol are 1α, 25-dihydroxycholecalciferol, 1,25-dihydroxyvitamin D 3 ,1,25-DHCC, 1,25(OH) 2 D 3 and 1,25-diOHC.

Structural Formula

HOW SUPPLIED

Repackaged by Aphena Pharma Solutions – TN.

See Repackaging Information for available configurations.

Calcitriol Capsules are supplied as oval, soft gelatin capsules.

The 0.25 mcg capsules are imprinted with “547” in black ink.

0054-0007-13 – 0.25 mcg yellow capsule, bottle of 30 0054-0007-25 – 0.25 mcg yellow capsule, bottle of 100 Calcitriol Capsules should be protected from light.

GERIATRIC USE

Geriatric Use Clinical studies of calcitriol 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.

INDICATIONS AND USAGE

Predialysis Patients Calcitriol Capsules are indicated in the management of secondary hyperparathyroidism and resultant metabolic bone disease in patients with moderate to severe chronic renal failure (Ccr 15 to 55 mL/min) not yet on dialysis.

In children, the creatinine clearance value must be corrected for a surface area of 1.73 square meters.

A serum iPTH level of ≥100 pg/mL is strongly suggestive of secondary hyperparathyroidism.

Dialysis Patients Calcitriol Capsules are indicated in the management of hypocalcemia and the resultant metabolic bone disease in patients undergoing chronic renal dialysis.

In these patients, calcitriol administration enhances calcium absorption, reduces serum alkaline phosphatase levels, and may reduce elevated parathyroid hormone levels and the histological manifestations of osteitis fibrosa cystica and defective mineralization.

Hypoparathyroidism Patients Calcitriol Capsules are also indicated in the management of hypocalcemia and its clinical manifestations in patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism.

PEDIATRIC USE

Pediatric Use Safety and effectiveness of calcitriol in pediatric patients undergoing dialysis have not been established.

The safety and effectiveness of calcitriol in pediatric predialysis patients is based on evidence from adequate and well-controlled studies of calcitriol in adults with predialysis chronic renal failure and additional supportive data from non-placebo controlled studies in pediatric patients.

Dosing guidelines have not been established for pediatric patients under 1 year of age with hypoparathyroidism or for pediatric patients less than 6 years of age with pseudohypoparathyroidism (see DOSAGE AND ADMINISTRATION : Hypoparathyroidism ).

Oral doses of calcitriol ranging from 10 to 55 ng/kg/day have been shown to improve calcium homeostasis and bone disease in pediatric patients with chronic renal failure for whom hemodialysis is not yet required (predialysis).

Long-term calcitriol therapy is well tolerated by pediatric patients.

The most common safety issues are mild, transient episodes of hypercalcemia, hyperphosphatemia, and increases in the serum calcium times phosphate (Ca x P) product which are managed effectively by dosage adjustment or temporary discontinuation of the vitamin D derivative.

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy Category C Calcitriol has been found to be teratogenic in rabbits when given at doses of 0.08 and 0.3 mcg/kg (approximately 2 and 6 times the maximum recommended dose based on mg/m 2 ).

All 15 fetuses in 3 litters at these doses showed external and skeletal abnormalities.

However, none of the other 23 litters (156 fetuses) showed external and skeletal abnormalities compared with controls.

Teratogenicity studies in rats at doses up to 0.45 mcg/kg (approximately 5 times maximum recommended dose based on mg/m 2 ) showed no evidence of teratogenic potential.

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

Calcitriol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects In the rabbit, dosages of 0.3 mcg/kg/day (approximately 6 times maximum recommended dose based on surface area) administered on days 7 to 18 of ges-tation resulted in 19% maternal mortality, a decrease in mean fetal body weight and a reduced number of newborn surviving to 24 hours.

A study of perinatal and postnatal development in rats resulted in hypercalcemia in the offspring of dams given calcitriol at doses of 0.08 or 0.3 mcg/kg/day (approximately 1 and 3 times the maximum recommended dose based on mg/m 2 ), hypercalcemia and hypophosphatemia in dams given calcitriol at a dose of 0.08 or 0.3 mcg/kg/day, and increased serum urea nitrogen in dams given calcitriol at a dose of 0.3 mcg/kg/day.

In another study in rats, maternal weight gain was slightly reduced at a dose of 0.3 mcg/kg/day (approximately 3 times the maximum recommended dose based on mg/m 2 ) administered on days 7 to 15 of gestation.

The offspring of a woman administered 17 mcg/day to 36 mcg/day of calcitriol (approximately 17 to 36 times the maximum recommended dose), during pregnancy manifested mild hypercalcemia in the first 2 days of life which returned to normal at day 3.

Nursing Mothers Calcitriol from ingested calcitriol capsules may be excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from calcitriol in nursing infants, a mother should not nurse while taking calcitriol capsules.

Pediatric Use Safety and effectiveness of calcitriol in pediatric patients undergoing dialysis have not been established.

Long-term calcitriol therapy is well tolerated by pediatric patients.

Geriatric Use Clinical studies of calcitriol 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.

NUSRING MOTHERS

Nursing Mothers Calcitriol from ingested calcitriol capsules may be excreted in human milk.

INFORMATION FOR PATIENTS

Information for Patients The patient and his or her caregivers should be informed about compliance with dosage instructions, adherence to instructions about diet and calcium supplementation, and avoidance of the use of unapproved nonprescription drugs.

Patients and their caregivers should also be carefully informed about the symptoms of hypercalcemia (see ADVERSE REACTIONS ).

The effectiveness of calcitriol therapy is predicated on the assumption that each patient is receiving an adequate daily intake of calcium.

Patients are advised to have a dietary intake of calcium at a minimum of 600 mg daily.

The U.S.

RDA for calcium in adults is 800 mg to 1200 mg.

DOSAGE AND ADMINISTRATION

The optimal daily dose of calcitriol must be carefully determined for each patient.

Calcitriol Capsules should be administered orally.

Calcitriol therapy should always be started at the lowest possible dose and should not be increased without careful monitoring of serum calcium.

The effectiveness of calcitriol therapy is predicated on the assumption that each patient is receiving an adequate but not excessive daily intake of calcium.

Patients are advised to have a dietary intake of calcium at a minimum of 600 mg daily.

The U.S.

RDA for calcium in adults is 800 mg to 1200 mg.

To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in proper dietary measures.

Because of improved calcium absorption from the gastrointestinal tract, some patients on calcitriol may be maintained on a lower calcium intake.

Patients who tend to develop hypercalcemia may require only low doses of calcium or no supplements at all.

During the titration period of treatment with calcitriol, serum calcium levels should be checked at least twice weekly.

When the optimal dosage of calcitriol has been determined, serum calcium levels should be checked every month (or as given below for individual indications).

Samples for serum calcium estimation should be taken without a tourniquet.

Dialysis Patients The recommended initial dose of calcitriol is 0.25 mcg/day.

If a satisfactory response in the biochemical parameters and clinical manifestations of the disease state is not observed, dosage may be increased by 0.25 mcg/day at 4 to 8 week intervals.

During this titration period, serum calcium levels should be obtained at least twice weekly, and if hypercalcemia is noted, the drug should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS : General ).

Phosphorus, magnesium, and alkaline phosphatase should be determined periodically.

Patients with normal or only slightly reduced serum calcium levels may respond to calcitriol doses of 0.25 mcg every other day.

Most patients undergoing hemodialysis respond to doses between 0.5 and 1 mcg/day.

Oral calcitriol may normalize plasma ionized calcium in some uremic patients, yet fail to suppress parathyroid hyperfunction.

In these individuals with autonomous parathyroid hyperfunction, oral calcitriol may be useful to maintain normocalcemia, but has not been shown to be adequate treatment for hyperparathyroidism.

Hypoparathyroidism The recommended initial dosage of calcitriol is 0.25 mcg/day given in the morning.

If a satisfactory response in the biochemical parameters and clinical manifestations of the disease is not observed, the dose may be increased at 2- to 4-week intervals.

During the dosage titration period, serum calcium levels should be obtained at least twice weekly and, if hypercalcemia is noted, calcitriol should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS : General ).

Careful consideration should also be given to lowering the dietary calcium intake.

Serum calcium, phosphorus, and 24-hour urinary calcium should be determined periodically.

Most adult patients and pediatric patients age 6 years and older have responded to dosages in the range of 0.5 mcg to 2 mcg daily.

Pediatric patients in the 1 to 5 year age group with hypoparathyroidism have usually been given 0.25 mcg to 0.75 mcg daily.

The number of treated patients with pseudohypoparathyroidism less than 6 years of age is too small to make dosage recommendations.

Malabsorption is occasionally noted in patients with hypoparathyroidism; hence, larger doses of calcitriol may be needed.

Predialysis Patients The recommended initial dosage of calcitriol is 0.25 mcg/day in adults and pediatric patients 3 years of age and older.

This dosage may be increased if necessary to 0.5 mcg/day.

For pediatric patients less than 3 years of age, the recommended initial dosage of calcitriol is 10 to 15 ng/kg/day.

Aztreonam 2000 MG Injection

WARNINGS

Both animal and human data suggest that AZACTAM (aztreonam injection) is rarely cross-reactive with other beta-lactam antibiotics and weakly immunogenic.

Treatment with aztreonam can result in hypersensitivity reactions in patients with or without prior exposure.

(See CONTRAINDICATIONS .) Careful inquiry should be made to determine whether the patient has any history of hypersensitivity reactions to any allergens.

While cross-reactivity of aztreonam with other beta-lactam antibiotics is rare, this drug should be administered with caution to any patient with a history of hypersensitivity to beta-lactams (eg, penicillins, cephalosporins, and/or carbapenems).

Treatment with aztreonam can result in hypersensitivity reactions in patients with or without prior exposure to aztreonam.

If an allergic reaction to aztreonam occurs, discontinue the drug and institute supportive treatment as appropriate (eg, maintenance of ventilation, pressor amines, antihistamines, corticosteroids).

Serious hypersensitivity reactions may require epinephrine and other emergency measures.

(See ADVERSE REACTIONS .) Clostridium difficile –associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including AZACTAM, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.

difficile .

difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin-producing strains of C.

difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.

difficile , and surgical evaluation should be instituted as clinically indicated.

Rare cases of toxic epidermal necrolysis have been reported in association with aztreonam in patients undergoing bone marrow transplant with multiple risk factors including sepsis, radiation therapy, and other concomitantly administered drugs associated with toxic epidermal necrolysis.

PRECAUTIONS General Prescribing AZACTAM in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

In patients with impaired hepatic or renal function, appropriate monitoring is recommended during therapy.

If an aminoglycoside is used concurrently with aztreonam, especially if high dosages of the former are used or if therapy is prolonged, renal function should be monitored because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics.

The use of antibiotics may promote the overgrowth of nonsusceptible organisms, including Gram-positive organisms ( Staphylococcus aureus and Streptococcus faecalis ) and fungi.

Should superinfection occur during therapy, appropriate measures should be taken.

Information for Patients Patients should be counseled that antibacterial drugs including AZACTAM should only be used to treat bacterial infections.

They do not treat viral infections (eg, the common cold).

When AZACTAM is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by AZACTAM or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued.

Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibiotic.

If this occurs, patients should contact their physician as soon as possible.

Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with aztreonam have not been conducted using an intravenous route of administration.

A 104-week rat inhalation toxicology study to assess the carcinogenic potential of aztreonam demonstrated no drug-related increase in the incidence of tumors.

Rats were exposed to aerosolized aztreonam for up to 4 hours per day.

Peak plasma levels of aztreonam averaging approximately 6.8 mcg/mL were measured in rats at the highest dose level.

Genetic toxicology studies performed with aztreonam in vitro (Ames test, mouse lymphoma forward mutation assay, gene conversion assay, chromosome aberration assay in human lymphocytes) and in vivo (mouse bone marrow cytogenetic assay) did not reveal evidence of mutagenic or clastogenic potential.

A two-generation reproduction study in rats at daily doses of 150, 600, or 2400 mg/kg given prior to and during gestation and lactation, revealed no evidence of impaired fertility.

Based on body surface area, the high dose is 2.9-fold greater than the maximum recommended human dose (MRHD) for adults of 8 g per day.

There was a slightly reduced survival rate during the lactation period in the offspring of rats that received the high dose, but not in offspring of rats that received lower doses of aztreonam.

Pregnancy Pregnancy Category B In pregnant women, aztreonam crosses the placenta and enters the fetal circulation.

Developmental toxicity studies in pregnant rats and rabbits with daily doses of aztreonam up to 1800 and 1200 mg/kg, respectively, revealed no evidence of embryotoxicity or fetotoxicity or teratogenicity.

These doses, based on body surface area, are 2.2- and 2.9-fold greater than the MRHD for adults of 8 g per day.

A peri/postnatal study in rats revealed no drug-induced changes in any maternal, fetal, or neonatal parameters.

The highest dose used in this study, 1800 mg/kg/day, is 2.2 times the MRHD based on body surface area.

There are no adequate and well-controlled studies of aztreonam on human pregnancy outcomes.

Because animal reproduction studies are not always predictive of human response, aztreonam should be used during pregnancy only if clearly needed.

Nursing Mothers Aztreonam is excreted in human milk in concentrations that are less than 1% of concentrations determined in simultaneously obtained maternal serum; consideration should be given to temporary discontinuation of nursing and use of formula feedings.

Pediatric Use The safety and effectiveness of intravenous AZACTAM have been established in the age groups 9 months to 16 years.

Use of AZACTAM in these age groups is supported by evidence from adequate and well-controlled studies of AZACTAM in adults with additional efficacy, safety, and pharmacokinetic data from noncomparative clinical studies in pediatric patients.

Sufficient data are not available for pediatric patients under 9 months of age or for the following treatment indications/pathogens: septicemia and skin and skin-structure infections (where the skin infection is believed or known to be due to H.

influenzae type b).

In pediatric patients with cystic fibrosis, higher doses of AZACTAM may be warranted.

(See CLINICAL PHARMACOLOGY , DOSAGE AND ADMINISTRATION , and CLINICAL STUDIES .) Geriatric Use Clinical studies of AZACTAM did not include sufficient numbers of subjects aged 65 years 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.9-12 In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In elderly patients, the mean serum half-life of aztreonam increased and the renal clearance decreased, consistent with the age-related decrease in creatinine clearance.1-4 Since aztreonam is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments made accordingly (see DOSAGE AND ADMINISTRATION : Renal Impairment in Adult Patients and Dosage in the Elderly ).

AZACTAM contains no sodium.

OVERDOSAGE

If necessary, aztreonam may be cleared from the serum by hemodialysis and/or peritoneal dialysis.

DOSAGE AND ADMINISTRATION Dosage in Adult Patients AZACTAM, an intravenous solution in GALAXY plastic containers (PL 2040), is intended for intravenous use only.

Dosage should be determined by susceptibility of the causative organisms, severity and site of infection, and the condition of the patient.

Table 2: Azactam Dosage Guidelines for Adults* Type of Infection Dose Frequency (hours) Urinary tract infections 500 mg or 1 g 8 or 12 Moderately severe systemic infections 1 g or 2 g 8 or 12 Severe systemic or life-threatening infections 2 g 6 or 8 * Maximum recommended dose is 8 g per day.

Because of the serious nature of infections due to Pseudomonas aeruginosa , dosage of 2 g every six or eight hours is recommended, at least upon initiation of therapy, in systemic infections caused by this organism.

The intravenous route is recommended for patients requiring single doses greater than 1 g or those with bacterial septicemia, localized parenchymal abscess (eg, intra-abdominal abscess), peritonitis, or other severe systemic or life-threatening infections.

The duration of therapy depends on the severity of infection.

Generally, AZACTAM should be continued for at least 48 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained.

Persistent infections may require treatment for several weeks.

Doses smaller than those indicated should not be used.

Renal Impairment in Adult Patients Prolonged serum levels of aztreonam may occur in patients with transient or persistent renal insufficiency.

Therefore, the dosage of AZACTAM should be halved in patients with estimated creatinine clearances between 10 and 30 mL/min/1.73 m2 after an initial loading dose of 1 or 2 g.

When only the serum creatinine concentration is available, the following formula (based on sex, weight, and age of the patient) may be used to approximate the creatinine clearance (Clcr).

The serum creatinine should represent a steady state of renal function.

Males: Clcr = weight (kg) × (140−age) 72 × serum creatinine (mg/dL) Females: 0.85 × above value In patients with severe renal failure (creatinine clearance less than 10 mL/min/1.73 m 2 ), such as those supported by hemodialysis, the usual dose of 500 mg, 1 g, or 2 g should be given initially.

The maintenance dose should be one-fourth of the usual initial dose given at the usual fixed interval of 6, 8, or 12 hours.

For serious or life-threatening infections, in addition to the maintenance doses, one-eighth of the initial dose should be given after each hemodialysis session.

Dosage in the Elderly Renal status is a major determinant of dosage in the elderly; these patients in particular may have diminished renal function.

Serum creatinine may not be an accurate determinant of renal status.

Therefore, as with all antibiotics eliminated by the kidneys, estimates of creatinine clearance should be obtained and appropriate dosage modifications made if necessary.

Dosage in Pediatric Patients AZACTAM should be administered intravenously to pediatric patients with normal renal function.

There are insufficient data regarding intramuscular administration to pediatric patients or dosing in pediatric patients with renal impairment.

(See PRECAUTIONS : Pediatric Use.

) Table 3: Azactam Dosage Guidelines for Pediatric Patients* Type of Infection Dose Frequency (hours) Mild to moderate infections 30 mg/kg 8 Moderate to severe infections 30 mg/kg 6 or 8 * Maximum recommended dose is 120 mg/kg/day.

CLINICAL STUDIES A total of 612 pediatric patients aged 1 month to 12 years were enrolled in uncontrolled clinical trials of aztreonam in the treatment of serious Gram-negative infections, including urinary tract, lower respiratory tract, skin and skin-structure, and intra-abdominal infections.

Directions for Use of AZACTAM (aztreonam injection) in GALAXY Plastic Container (PL 2040).

AZACTAM is to be administered as an intermittent intravenous infusion only.

Storage Store in a freezer capable of maintaining a temperature of −20°C (−4°F).

Thawing of Plastic Containers Thaw frozen container at room temperature, 25°C (77°F) or in a refrigerator, 2°C to 8°C (36°F-46°F).

After thawing is complete, invert the container to assure a well-mixed solution.

( DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION.) Check for minute leaks by squeezing container firmly.

If leaks are detected, discard solution as sterility may be impaired.

The container should be visually inspected.

Thawed solutions should not be used unless clear; solutions will be colorless to yellow.

Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation.

If after visual inspection the solution remains discolored, cloudy, or if an insoluble precipitate is noted or if any seals or outlet ports are not intact, the container should be discarded.

DO NOT ADD SUPPLEMENTARY MEDICATION.

T he thawed solution in GALAXY plastic container (PL 2040) remains chemically stable for either 14 days under refrigeration (2°C-8°C/36°F-46°F) or for 48 hours at room temperature (25°C/77°F).

DO NOT REFREEZE THAWED ANTIBIOTICS.

Preparation for Intravenous Administration Use aseptic technique.

Suspend container(s) from eyelet support.

Remove protector from outlet port at bottom of container.

Attach administration set.

Refer to complete directions accompanying set.

Additives or other medication should not be added to AZACTAM or infused simultaneously through the same intravenous line.

If the same intravenous line is used for sequential infusion of several different drugs, it should be flushed before and after infusion of AZACTAM with an infusion solution compatible with AZACTAM (aztreonam injection) in GALAXY plastic container (PL 2040)* and any other drug(s) administered via this common line.

It is recommended that the intravenous administration apparatus be replaced at least once every 48 hours.

CAUTION: Do not use plastic containers in series connections.

Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Intravenous Administration Infusion of AZACTAM should be completed within a 20- to 60-minute period.

The plastic container is a single-dose unit; discard any unused portion remaining in the container.

*The following infusion solutions are compatible with AZACTAM (aztreonam injection) in GALAXY plastic container (PL 2040): Sodium Chloride Injection, USP, 0.9% Ringer’s Injection, USP Lactated Ringer’s Injection, USP Dextrose Injection, USP, 5% or 10% Dextrose and Sodium Chloride Injection, USP, 5%:0.9%, 5%:0.45%, or 5%:0.2% Sodium Lactate Injection, USP (M/6 Sodium Lactate) Ionosol ® B and 5% Dextrose Isolyte ® E Isolyte ® E with 5% Dextrose Isolyte ® M with 5% Dextrose Normosol ® -R Normosol ® -R and 5% Dextrose Normosol ® -M and 5% Dextrose Mannitol Injection, USP, 5% or 10% Lactated Ringer’s and 5% Dextrose Injection Plasma-Lyte M and 5% Dextrose

DESCRIPTION

AZACTAM ® (aztreonam injection) contains the active ingredient aztreonam, a monobactam.

It was originally isolated from Chromobacterium violaceum .

It is a synthetic bactericidal antibiotic.

The monobactams, having a unique monocyclic beta-lactam nucleus, are structurally different from other beta-lactam antibiotics (eg, penicillins, cephalosporins, cephamycins).

The sulfonic acid substituent in the 1-position of the ring activates the beta-lactam moiety; an aminothiazolyl oxime side chain in the 3-position and a methyl group in the 4-position confer the specific antibacterial spectrum and beta-lactamase stability.

Aztreonam is designated chemically as (Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid.

Structural formula: C 13 H 17 N 5 O 8 S 2 MW 435.44 AZACTAM in the GALAXY plastic container (PL 2040) is a frozen, iso-osmotic, sterile, sodium-free, nonpyrogenic intravenous solution.

Each 50 mL of solution contains 1 g, or 2 g aztreonam with approximately 1.7 g, or 700 mg Dextrose Hydrous, USP added to adjust osmolality, and approximately 780 mg, or 1.6 g of arginine added for pH adjustment, respectively.

Thawed solutions have a pH in the range of 4.5 to 7.5.

The solution is for intravenous administration following thawing at room temperature or under refrigeration.

This GALAXY container is fabricated from a specially designed multilayer plastic (PL 2040).

Solutions are in contact with the polyethylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period.

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

Azactam Galaxy Chemical Structure

HOW SUPPLIED

AZACTAM ® (aztreonam injection) in GALAXY plastic container (PL 2040) is supplied as a frozen, 50 mL single-dose intravenous solution as follows: 1 g aztreonam/50 mL container: Packages of 24 NDC 0003-2230-11 2 g aztreonam/50 mL container: Packages of 24 NDC 0003-2240-11 Store at or below –20°C (–4°F) [see Directions for Use of AZACTAM (aztreonam injection) in GALAXY Plastic Container (PL 2040) ].

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AZACTAM (aztreonam injection) and other antibacterial drugs, AZACTAM should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

AZACTAM is indicated for the treatment of the following infections caused by susceptible Gram-negative microorganisms: Urinary Tract Infections (complicated and uncomplicated), including pyelonephritis and cystitis (initial and recurrent) caused by Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , Pseudomonas aeruginosa , Enterobacter cloacae , Klebsiella oxytoca *, Citrobacter species*, and Serratia marcescens *.

Lower Respiratory Tract Infections , including pneumonia and bronchitis caused by Escherichia coli , Klebsiella pneumoniae , Pseudomonas aeruginosa , Haemophilus influenzae , Proteus mirabilis , Enterobacter species, and Serratia marcescens *.

Septicemia caused by Escherichia coli , Klebsiella pneumoniae , Pseudomonas aeruginosa , Proteus mirabilis *, Serratia marcescens *, and Enterobacter species.

Skin and Skin-Structure Infections , including those associated with postoperative wounds, ulcers, and burns, caused by Escherichia coli , Proteus mirabilis , Serratia marcescens , Enterobacter species, Pseudomonas aeruginosa , Klebsiella pneumoniae , and Citrobacter species*.

Intra-abdominal Infections , including peritonitis caused by Escherichia coli , Klebsiella species including K.

pneumoniae , Enterobacter species including E.

cloacae *, Pseudomonas aeruginosa , Citrobacter species* including C.

freundii *, and Serratia species* including S.

marcescens *.

Gynecologic Infections , including endometritis and pelvic cellulitis caused by Escherichia coli , Klebsiella pneumoniae *, Enterobacter species* including E.

cloacae *, and Proteus mirabilis *.

AZACTAM is indicated for adjunctive therapy to surgery in the management of infections caused by susceptible organisms, including abscesses, infections complicating hollow viscus perforations, cutaneous infections, and infections of serous surfaces.

AZACTAM is effective against most of the commonly encountered Gram-negative aerobic pathogens seen in general surgery.

———————————— * Efficacy for this organism in this organ system was studied in fewer than 10 infections.

Concurrent Therapy Concurrent initial therapy with other antimicrobial agents and AZACTAM is recommended before the causative organism(s) is known in seriously ill patients who are also at risk of having an infection due to Gram-positive aerobic pathogens.

If anaerobic organisms are also suspected as etiologic agents, therapy should be initiated using an anti-anaerobic agent concurrently with AZACTAM (see DOSAGE AND ADMINISTRATION ).

Certain antibiotics (eg, cefoxitin, imipenem) may induce high levels of beta-lactamase in vitro in some Gram-negative aerobes such as Enterobacter and Pseudomonas species, resulting in antagonism to many beta-lactam antibiotics including aztreonam.

These in vitro findings suggest that such beta-lactamase inducing antibiotics not be used concurrently with aztreonam.

Following identification and susceptibility testing of the causative organism(s), appropriate antibiotic therapy should be continued.

PREGNANCY

Pregnancy Pregnancy Category B In pregnant women, aztreonam crosses the placenta and enters the fetal circulation.

These doses, based on body surface area, are 2.2- and 2.9-fold greater than the MRHD for adults of 8 g per day.

A peri/postnatal study in rats revealed no drug-induced changes in any maternal, fetal, or neonatal parameters.

The highest dose used in this study, 1800 mg/kg/day, is 2.2 times the MRHD based on body surface area.

There are no adequate and well-controlled studies of aztreonam on human pregnancy outcomes.

Because animal reproduction studies are not always predictive of human response, aztreonam should be used during pregnancy only if clearly needed.

Pediatric Use The safety and effectiveness of intravenous AZACTAM have been established in the age groups 9 months to 16 years.

influenzae type b).

In pediatric patients with cystic fibrosis, higher doses of AZACTAM may be warranted.

AZACTAM contains no sodium.

Pilocarpine Hydrochloride 5 MG Oral Tablet

WARNINGS

Cardiovascular Disease Patients with significant cardiovascular disease may be unable to compensate for transient changes in hemodynamics or rhythm induced by pilocarpine.

Pulmonary edema has been reported as a complication of pilocarpine toxicity from high ocular doses given for acute angle-closure glaucoma.

Pilocarpine should be administered with caution in and under close medical supervision of patients with significant cardiovascular disease.

Ocular Ocular formulations of pilocarpine have been reported to cause visual blurring which may result in decreased visual acuity, especially at night and in patients with central lens changes, and to cause impairment of depth perception.

Caution should be advised while driving at night or performing hazardous activities in reduced lighting.

Pulmonary Disease Pilocarpine has been reported to increase airway resistance, bronchial smooth muscle tone, and bronchial secretions.

Pilocarpine hydrochloride should be administered with caution to and under close medical supervision in patients with controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease requiring pharmacotherapy.

DRUG INTERACTIONS

Drug Interactions Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances.

Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects.

Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly.

These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium).

While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sjogren’s efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone.

OVERDOSAGE

MANAGEMENT OF OVERDOSE Fatal overdosage with pilocarpine has been reported in the scientific literature at doses presumed to be greater than 100 mg in two hospitalized patients.

100 mg of pilocarpine is considered potentially fatal.

Overdosage should be treated with atropine titration (0.5 mg to 1.0 mg given subcutaneously or intravenously) and supportive measures to maintain respiration and circulation.

Epinephrine (0.3 mg to 1.0 mg, subcutaneously or intramuscularly) may also be of value in the presence of severe cardiovascular depression or bronchoconstriction.

It is not known if pilocarpine is dialyzable.

DESCRIPTION

Pilocarpine hydrochloride tablets, USP contain pilocarpine hydrochloride, a cholinergic agonist for oral use.

Pilocarpine hydrochloride, USP is a hygroscopic, odorless, bitter tasting white crystal or powder, which is soluble in water and alcohol and virtually insoluble in most non-polar solvents.

Pilocarpine hydrochloride, USP with a chemical name of (3S- cis )-2(3 H )-Furanone, 3-ethyldihydro-4-[(1-methyl-1 H -imidazol-5-yl) methyl] monohydrochloride, has a molecular weight of 244.72.

Each 5 mg Pilocarpine Hydrochloride Tablet, USP for oral administration contains 5 mg of pilocarpine hydrochloride.

Inactive ingredients in the tablet are microcrystalline cellulose and stearic acid, the tablet’s film coating is: polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

Each 7.5 mg Pilocarpine Hydrochloride Tablet, USP for oral administration contains 7.5 mg of pilocarpine hydrochloride.

Inactive ingredients in the tablet are microcrystalline cellulose and stearic acid, the tablet’s film coating is: FD&C Blue #2/Indigo Carmine aluminum lake, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

The chemical structure of Pilocarpine hydrochloride.

CLINICAL STUDIES

Clini cal Studies Head & Neck Cancer Patients A 12 week randomized, double-blind, placebo-controlled study in 207 patients (142 men, 65 women) was conducted in patients whose mean age was 58.5 years with a range of 19 to 77; the racial distribution was Caucasian 95%, Black 4%, and other 1%.

In this population, a statistically significant improvement in mouth dryness occurred in the 5 and 10 mg pilocarpine hydrochloride tablet treated patients compared to placebo treated patients.

The 5 and 10 mg treated patients could not be distinguished.

(See Pharmacodynamics section for flow study details.) Another 12 week, double-blind, randomized, placebo-controlled study was conducted in 162 patients whose mean age was 57.8 years with a range of 27 to 80; the racial distribution was Caucasian 88%, Black 10%, and other 2%.

The effects of placebo were compared to 2.5 mg three times a day of pilocarpine hydrochloride tablets for 4 weeks followed by adjustment to 5 mg three times a day and 10 mg three times a day.

Lowering of the dose was necessary because of adverse events in 3 of 67 patients treated with 5 mg of pilocarpine hydrochloride tablets and in 7 of 66 patients treated with 10 mg of pilocarpine hydrochloride tablets.

After 4 weeks of treatment, 2.5 mg of pilocarpine hydrochloride tablets three times a day was comparable to placebo in relieving dryness.

In patients treated with 5 mg and 10 mg of pilocarpine hydrochloride tablets, the greatest improvement in dryness was noted in patients with no measurable salivary flow at baseline.

In both studies, some patients noted improvement in the global assessment of their dry mouth, speaking without liquids, and a reduced need for supplemental oral comfort agents.

In the two placebo-controlled clinical trials, the most common adverse events related to drug, and increasing in rate as dose increases, were sweating, nausea, rhinitis, diarrhea, chills, flushing, urinary frequency, dizziness, and asthenia.

The most common adverse experience causing withdrawal from treatment was sweating (5 mg t.i.d.

≤1%; 10 mg t.i.d.

=12%).

Sjogren’s Syndrome Patients Two separate studies were conducted in patients with primary or secondary Sjogren’s Syndrome.

In both studies, the majority of patients best fit the European criteria for having primary Sjogren’s Syndrome.

[“Criteria for the Classification of Sjogren’s Syndrome” (Vitali C, Bombardieri S, Moutsopoulos HM, et al: Preliminary criteria for the classification of Sjogren’s syndrome.

Arthritis Rheum 36:340-347, 1993.)] A twelve week, randomized, double-blind, parallel-group, placebo-controlled study was conducted in 256 patients (14 men, 242 women) whose mean age was 57 years with a range of 24 to 85 years.

The racial distribution was as follows: Caucasian 91%, Black 6%, and other 3%.

The effects of placebo were compared with those of pilocarpine hydrochloride tablets 5 mg four times a day (20 mg/day) for 6 weeks.

At 6 weeks, the patients’ dosage was increased from 5 mg pilocarpine hydrochloride tablets q.i.d.

to 7.5 mg q.i.d.

The data collected during the first 6 weeks of the trial were evaluated for safety and efficacy, and the data of the second 6 weeks of the trial were used to provide additional evidence of safety.

After 6 weeks of treatment, statistically significant global improvement of dry mouth was observed compared to placebo.

“Global improvement” is defined as a score of 55 mm or more on a 100 mm visual analogue scale in response to the question, “Please rate your present condition of dry mouth (xerostomia) compared with your condition at the start of this study.

Consider the changes to your dry mouth and other symptoms related to your dry mouth that have occurred since you have taken this medication.” Patients’ assessments of specific dry mouth symptoms such as severity of dry mouth, mouth discomfort, ability to speak without water, ability to sleep without drinking water, ability to swallow food without drinking, and a decreased use of saliva substitutes were found to be consistent with the significant global improvement described.

Another 12 week randomized, double-blind, parallel-group, placebo-controlled study was conducted in 373 patients (16 men, 357 women) whose mean age was 55 years with a range of 21 to 84.

The racial distribution was Caucasian 80%, Oriental 14%, Black 2%, and 4% of other origin.

The treatment groups were 2.5 mg pilocarpine tablets, 5 mg pilocarpine hydrochloride tablets, and placebo.

All treatments were administered on a four times a day regimen.

After 12 weeks of treatment, statistically significant global improvement of dry mouth was observed at a dose of 5 mg compared with placebo.

The 2.5 mg (10mg/day) group was not significantly different than placebo.

However, a subgroup of patients with rheumatoid arthritis tended to improve in global assessments at both the 2.5 mg q.i.d.

(9 patients) and 5 mg q.i.d.

(16 patients) dose (10-20 mg/day).

The clinical significance of this finding is unknown.

Patients’ assessments of specific dry mouth symptoms such as severity of dry mouth, mouth discomfort, ability to sleep without drinking water, and decreased use of saliva substitutes were also found to be consistent with the significant global improvement described when measured after 6 weeks and 12 weeks of pilocarpine hydrochloride tablets use.

HOW SUPPLIED

Pilocarpine hydrochloride tablets USP, 5 mg are white, film coated, round tablets, debossed LAN on one side and 1313 on the other side.

Each tablet contains 5 mg pilocarpine hydrochloride.

They are supplied as follows: Bottles of 100; NDC 10135-0589-01 Store at 20°- 25°C (68°-77°F) [see USP Controlled Room Temperature].

Pilocarpine hydrochloride tablets USP, 7.5 mg are blue, film coated, round tablets, debossed LCI on one side and 1407 on the other side.

Each tablet contains 7.5 mg pilocarpine hydrochloride.

They are supplied as follows: Bottles of 100; NDC 10135-0590-01 Store at 20°- 25°C (68°-77°F) [see USP Controlled Room Temperature].

Manufactured by: Lannett Company, Inc.

Philadelphia, PA 19136 Distributed By: Marlex Pharmaceuticals, Inc.

New Castle, DE 19720 Made in the USA Rev.

10/14 LAN

GERIATRIC USE

Geriatric Use Head and Neck Cancer Patients In the placebo-controlled clinical trials (see Clinical Studies section) the mean age of patients was approximately 58 years (range 19 to 80).

Of these patients, 97/369 (61/217 receiving pilocarpine) were over the age of 65 years.

In the healthy volunteer studies, 15/150 subjects were over the age of 65 years.

In both study populations, the adverse events reported by those over 65 years and those 65 years and younger were comparable.

Of the 15 elderly volunteers (5 women, 10 men), the 5 women had higher C max and AUC’s than the men.

(See Pharmacokinetics section.) Sjogren’s Syndrome Patients In the placebo-controlled clinical trials (see Clinical Studies section), the mean age of patients was approximately 55 years (range 21 to 85).

The adverse events reported by those over 65 years and those 65 years and younger were comparable except for notable trends for urinary frequency, diarrhea, and dizziness (see ADVERSE REACTIONS section).

INDICATIONS AND USAGE

INDICATIONS AN D USAGE Pilocarpine hydrochloride tablets, USP are indicated for 1) the treatment of symptoms of dry mouth from salivary gland hypofunction caused by radiotherapy for cancer of the head and neck; and 2) the treatment of symptoms of dry mouth in patients with Sjogren’s syndrome.

PEDIATRIC USE

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

PREGNANCY

Pregnancy Teratogenic effects Pregnancy Category C Pilocarpine was associated with a reduction in the mean fetal body weight and an increase in the incidence of skeletal variations when given to pregnant rats at a dosage of 90 mg/kg/day (approximately 26 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m 2 ) estimates).

These effects may have been secondary to maternal toxicity.

In another study, oral administration of pilocarpine to female rats during gestation and lactation at a dosage of 36 mg/kg/day (approximately 10 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m 2 ) estimates) resulted in an increased incidence of stillbirths; decreased neonatal survival and reduced mean body weight of pups were observed at dosages of 18 mg/kg/day (approximately 5 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m 2 ) estimates) and above.

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

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

NUSRING MOTHERS

Nursing Mothers It is not known whether this drug 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 pilocarpine hydrochloride tablets, 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 Patients should be informed that pilocarpine may cause visual disturbances, especially at night, that could impair their ability to drive safely.

If a patient sweats excessively while taking pilocarpine hydrochloride and cannot drink enough liquid, the patient should consult a physician.

Dehydration may develop.

DOSAGE AND ADMINISTRATION

Regardless of the indication, the starting dose in patients with moderate hepatic impairment should be 5 mg twice daily, followed by adjustment based on therapeutic response and tolerability.

Patients with mild hepatic insufficiency do not require dosage reductions.

The use of pilocarpine in patients with severe hepatic insufficiency is not recommended.

If needed, refer to the Hepatic Insufficiency subsection of the Precautions section of this label for definitions of mild, moderate and severe hepatic impairment.

Head & Neck Cancer Patients The recommended initial dose of pilocarpine hydrochloride tablets is 5 mg taken three times a day.

Dosage should be titrated according to therapeutic response and tolerance.

The usual dosage range is up to 15-30 mg per day.

(Not to exceed 10 mg per dose.) Although early improvement may be realized, at least 12 weeks of uninterrupted therapy with pilocarpine hydrochloride tablets may be necessary to assess whether a beneficial response will be achieved.

The incidence of the most common adverse events increases with dose.

The lowest dose that is tolerated and effective should be used for maintenance.

Sjogren’s Syndrome Patients The recommended dose of pilocarpine hydrochloride tablets is 5 mg taken four times a day.

Efficacy was established by 6 weeks of use.

tretinoin 0.1 % Topical Gel

Generic Name: TRETINOIN

Brand Name: Retin-A MICRO

Substance Name(s):
TRETINOIN

OVERDOSAGE

10 Oral ingestion of large amounts of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A.

DESCRIPTION

11 Retin-A Micro (tretinoin) Gel microsphere, 0.1%, 0.08%, 0.06% and 0.04% is a white to very pale yellow opaque gel for topical treatment of acne vulgaris.

Chemically, tretinoin is all-trans-retinoic acid, also known as (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid.

It is a member of the retinoid class of compounds and a metabolite of naturally occurring Vitamin A.

Tretinoin has a molecular weight of 300.44, a molecular formula of C 20 H 28 O 2 and the following chemical structure: Each gram of Retin-A Micro Gel, 0.1%, contains 1 mg of tretinoin.

Each gram of Retin-A Micro Gel, 0.08%, contains 0.8 mg of tretinoin.

Each gram of Retin-A Micro Gel, 0.06%, contains 0.6 mg of tretinoin.

Each gram of Retin-A Micro Gel, 0.04%, contains 0.4 mg of tretinoin.

The formulation uses methyl methacrylate/glycol dimethacrylate crosspolymer porous microspheres (MICROSPONGE ® System) to enable inclusion of the active ingredient, tretinoin, in an aqueous gel.

Other components consist of benzyl alcohol, butylated hydroxytoluene, carbomer 974P, cyclomethicone and dimethicone copolyol, disodium EDTA, glycerin, PPG-20 methyl glucose ether distearate, propylene glycol, purified water, sorbic acid, and trolamine.

Tretinoin Chemical Structure

CLINICAL STUDIES

14 14.1 Retin-A Micro (tretinoin) Gel microsphere, 0.1% In two vehicle-controlled trials, Retin-A Micro (tretinoin) Gel microsphere, 0.1%, applied once daily was significantly more effective than vehicle in reducing the acne lesion counts.

The mean reductions in lesion counts from baseline after treatment for 12 weeks are shown in the following table: Table 1: Mean Percent Reduction in Lesion Counts Retin-A Micro (tretinoin) Gel microsphere, 0.1% Retin-A Micro (tretinoin) Gel microsphere, 0.1% Vehicle Gel Study #1 72 pts Study #2 71 pts Study #1 72 pts Study #2 67 pts Non-inflammatory lesion counts 49% 32% 22% 3% Inflammatory lesion counts 37% 29% 18% 24% Total lesion counts 45% 32% 23% 16% Retin-A Micro (tretinoin) Gel microsphere, 0.1%, was also significantly superior to the vehicle in the investigator’s global evaluation of the clinical response.

In Study #1, thirty-five percent (35%) of subjects using Retin-A Micro (tretinoin) Gel microsphere, 0.1%, achieved an excellent result, as compared to eleven percent (11%) of subjects on the vehicle control.

In Study #2, twenty-eight percent (28%) of patients using Retin-A Micro (tretinoin) Gel microsphere, 0.1%, achieved an excellent result, as compared to nine percent (9%) of the subjects on the vehicle control.

14.2 Retin-A Micro (tretinoin) Gel microsphere, 0.04% In two vehicle-controlled clinical trials, Retin-A Micro (tretinoin) Gel microsphere, 0.04%, applied once daily, was more effective (p<0.05) than vehicle in reducing the acne lesion counts.

The mean reductions in lesion counts from baseline after treatment for 12 weeks are shown in the following table: Table 2: Mean Percent Reduction in Lesion Counts Retin-A Micro (tretinoin) Gel microsphere, 0.04% Retin-A Micro (tretinoin) Gel microsphere, 0.04% Vehicle Gel Study #3 108 pts Study #4 111 pts Study #3 110 pts Study #4 103 pts Non-inflammatory lesion counts 37% 29% −2% – That is, a mean percent increase of 2% 14% Inflammatory lesion counts 44% 41% 13% 30% Total lesion counts 40% 35% 8% 20% Retin-A Micro (tretinoin) Gel microsphere, 0.04%, was also superior (p<0.05) to the vehicle in the investigator's global evaluation of the clinical response.

In Study #3, fourteen percent (14%) of subjects using Retin-A Micro (tretinoin) Gel microsphere, 0.04%, achieved an excellent result compared to five percent (5%) of subjects on vehicle control.

In Study #4, nineteen percent (19%) of subjects using Retin-A Micro (tretinoin) Gel microsphere, 0.04%, achieved an excellent result compared to nine percent (9%) of subjects on vehicle control.

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied Retin-A Micro Gel is opaque and white to very pale yellow in color.

Retin-A Micro Gel, 0.1%, is supplied in 20 gram tube (NDC 0187-5140-20), 45 gram tube (NDC 0187-5140-45) and 50 gram pump (NDC 0187-5140-50).

Retin-A Micro Gel, 0.08%, is supplied in 50 gram pump (NDC 0187-5148-50).

Retin-A Micro Gel, 0.06%, is supplied in 50 gram pump (NDC 0187-5146-50).

Retin-A Micro Gel, 0.04%, is supplied in 20 gram tube (NDC 0187-5144-20), 45 gram tube (NDC 0187-5144-45) and 50 gram pump (NDC 0187-5144-50).

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

Store pump upright.

Keep out of reach of children.

GERIATRIC USE

8.5 Geriatric Use Safety and effectiveness in a geriatric population have not been established.

Clinical trials of Retin-A Micro (tretinoin) Gel microsphere, 0.1% and 0.04%, did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects.

DOSAGE FORMS AND STRENGTHS

3 Retin-A Micro is a white to very pale yellow opaque gel.

Retin-A Micro is available in four strengths: 0.1%, 0.08%, 0.06% and 0.04%.

Each gram of Retin-A Micro Gel, 0.1%, contains 1 mg of tretinoin.

Each gram of Retin-A Micro Gel, 0.08%, contains 0.8 mg of tretinoin.

Each gram of Retin-A Micro Gel, 0.06%, contains 0.6 mg of tretinoin.

Each gram of Retin-A Micro Gel, 0.04%, contains 0.4 mg of tretinoin.

Gel, 0.1%, 0.08%, 0.06%, and 0.04% ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Although tretinoin activates three members of the retinoic acid (RAR) nuclear receptors (RARα, RARβ, and RARγ) which may act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation, it has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors and/or other mechanisms.

The exact mode of action of tretinoin is unknown.

Current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedone formation.

Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

INDICATIONS AND USAGE

1 Retin-A Micro ® is a retinoid indicated for topical application in the treatment of acne vulgaris.

Retin-A Micro is a retinoid, indicated for topical treatment of acne vulgaris.

( 1 )

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in children below the age of 12 have not been established.

PREGNANCY

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

Retin-A Micro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of tretinoin products.

Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain).

The significance of these spontaneous reports in terms of risk to the fetus is not known.

For purposes of comparison of the animal exposure to systemic human exposure, the MRHD applied topically is defined as 1 gram of Retin-A Micro (tretinoin) Gel microsphere, 0.1%, applied daily to a 60 kg person (0.017 mg tretinoin/kg body weight).

Pregnant rats were treated with Retin-A Micro (tretinoin) Gel microsphere, 0.1%, at daily dermal doses of 0.5 to 1.0 mg/kg/day tretinoin on gestation days 6-15.

Alterations were seen in vertebrae and ribs of offspring at 5 to 10 times the MRHD based on the body surface area (BSA) comparison.

Pregnant New Zealand White rabbits were treated with Retin-A Micro (tretinoin) Gel microsphere, 0.1%, at daily dermal doses of 0.2, 0.5, and 1.0 mg/kg/day tretinoin on gestation days 7-19.

Doses were administered topically for 24 hours a day while wearing Elizabethan collars to prevent ingestion of the drug.

Increased incidences of certain alterations, including domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species, were observed at 0.5 and 1.0 mg/kg/day.

Similar malformations were not observed at 0.2 mg/kg/day, 4 times the MRHD based on BSA comparison.

Other pregnant rabbits exposed topically for six hours per day to 0.5 or 1.0 mg/kg/day tretinoin while restrained in stocks to prevent ingestion, did not show any malformations at doses up to 19 times (1.0 mg/kg/day) the MRHD based on BSA comparison, but fetal resorptions were increased at 0.5 mg/kg (10 times the MRHD based on BSA comparison).

Oral tretinoin has been shown to cause malformations in rats, mice, rabbits, hamsters, and nonhuman primates.

Tretinoin induced fetal malformations in Wistar rats when given orally at doses greater than 1 mg/kg/day (10 times the MRHD based on BSA comparison).

In the cynomolgus monkey, fetal malformations were reported for doses of 10 mg/kg/day but none were observed at 5 mg/kg/day (95 times the MRHD based on BSA comparison), although increased skeletal variations were observed at all doses.

Dose-related increases in embryolethality and abortion also were reported.

Similar results have also been reported in pigtail macaques.

In oral peri- and postnatal development studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (19 times the MRHD based on BSA comparison).

Nonteratogenic effects on fetus Oral tretinoin has been shown to be fetotoxic in rats when administered at doses 24 times the MRHD based on BSA comparison.

Topical tretinoin has been shown to be fetotoxic in rabbits when administered at doses 10 times the MRHD based on BSA comparison.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether tretinoin and/or its metabolites are excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when Retin-A Micro is administered to a nursing woman.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Retin-A Micro should not be used on eczematous or sunburned skin due to potential for severe irritation.

( 5.1 , 5.2 ) Avoid unprotected exposure to sunlight including sunlamps (UV light), when using Retin-A Micro due to potential for increased photosensitization.

Use sunscreen of at least SPF 15 and protective clothing during exposure.

( 5.2 ) Avoid use of Retin-A Micro with weather extremes, such as wind or cold due to potential for increased irritation.

( 5.2 ) 5.1 Local Irritation The skin of certain individuals may become excessively dry, red, swollen, or blistered.

Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition.

If the degree of irritation warrants, patients should be directed to temporarily reduce the amount or frequency of application of the medication, discontinue use temporarily, or discontinue use all together.

Efficacy at reduced frequencies of application has not been established.

If a reaction suggesting sensitivity occurs, use of the medication should be discontinued.

To help limit skin irritation, patients must wash the treated skin gently, using a mild, non-medicated soap, and pat it dry, and avoid washing the treated skin too often or scrubbing it hard when washing.

Patients should apply a topical moisturizer if dryness is bothersome.

5.2 Exposure to Ultraviolet Light or Weather Extremes Unprotected exposure to sunlight, including sunlamps (UV light) should be avoided or minimized during the use of Retin-A Micro and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin.

Patients who may be required to have extended periods of UV exposure (e.g., due to occupation or sports), or those with inherent sensitivity to the sun, or those using medications that cause photosensitivity, should exercise particular caution.

Use of sunscreen products (SPF 15 or higher) and protective clothing over treated areas are recommended when exposure cannot be avoided [see Nonclinical Toxicology (13.1) ].

Weather extremes, such as wind or cold, also may be irritating to tretinoin-treated skin.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

The patient should be instructed to: Cleanse the treatment area thoroughly, before treatment, with a mild, non-medicated cleanser.

Do not use more than the recommended amount and do not apply Retin-A Micro more than once daily as this will not produce faster or better results, but may increase irritation.

Minimize exposure to sunlight, including sunlamps.

Recommend the use of sunscreen products and protective apparel (e.g., hat) when exposure cannot be avoided.

DOSAGE AND ADMINISTRATION

2 For topical use only.

Not for ophthalmic, oral, or intravaginal use.

Retin-A Micro should be applied once a day, in the evening, to the skin where acne lesions appear, using enough to cover the entire affected area in a thin layer.

Areas to be treated should be cleansed thoroughly before the medication is applied.

If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur.

A transitory feeling of warmth or slight stinging may be noted on application.

In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or the frequency of application increased as the patient becomes able to tolerate the treatment.

Frequency of application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance.

Efficacy has not been established for less than once daily dosing frequencies.

During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur.

If tolerated, this should not be considered a reason to discontinue therapy [see Adverse Reactions (6.1) ].

Therapeutic results may be noticed after two weeks, but more than seven weeks of therapy are required before consistent beneficial effects are observed.

Retin-A Micro should be kept away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes.

Patients treated with Retin-A Micro may use cosmetics.

Concomitant topical medication, medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, or spices should be used with caution because of possible interaction with tretinoin.

Avoid contact with the peel of limes.

Particular caution should be exercised with the concomitant use of topical over-the-counter acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with Retin-A Micro.

It also is advisable to allow the effects of such preparations to subside before use of Retin-A Micro is begun.

Apply a thin layer of Retin-A Micro once daily, before bedtime, to skin where lesions occur.

Keep away from eyes, mouth, nasal creases, and mucous membranes.

( 2 ) Not for oral, ophthalmic, or intravaginal use.

( 2 )

Acetaminophen 250 MG / Aspirin 250 MG / Caffeine 65 MG Oral Tablet

WARNINGS

Warnings Reye’s Syndrome: Children and teenagers who have or are recovering from chicken pox or flu like symptoms should not use this product.

When using this product, if changes in behavior with nausea and vomiting occur, consult a doctor because these symptoms could be an early sign of Reye’s syndrome, a rare but serious illness.

Allergy alert: Aspirin may cause a severe allergic reaction which may include: hives · facial swelling ·asthma (wheezing) · shock Liver Warning: This product contains acetaminophen.

Severe liver damage may occur if you take · more than 8 tablets in 24 hours, which is the maximum daily amount · with other drugs containing acetaminophen · 3 or more alcoholic drinks every day while using this product.

Stomach bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding.

The chance is higher if you ·are age 60 or older ·have had stomach ulcers or bleeding problems · take a blood thinning (anticoagulant) or steroid drug ·take other drugs containing prescription or nonprescription NSAIDs ( aspirin, ibuprofen, naproxen, or others) ·have 3 or more alcoholic drinks every day while using this product ·take more or for a longer time than directed.

Caffeine warning: The recommended dose of this product contains about as much caffeine as a cup of coffee.

Limit the use of caffeine-containing medications, foods, or beverages while taking this product because too much caffeine may cause nervousness, irritability, sleeplessness, and occasionally, rapid heartbeat.

INDICATIONS AND USAGE

Use(s) temporarily relieves minor headaches and pains due to: ●headache ● muscular aches ● premenstrual & menstrual cramps ● cold● sinusitis ● arthritis ● toothache

INACTIVE INGREDIENTS

Inactive ingredients Microcrystalline cellulose, Croscarmellose sodium, Stearic acid, Hypromellose, Traicetin, Titanium dioxide & Talc

PURPOSE

Purpose Pain reliever Pain reliever Pain reliever aid

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.

Quick medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms.

ASK DOCTOR

Ask a doctor before use if ·you have liver disease ·stomach bleeding warning applies to you ·you have a history of stomach problems, such as heart burn ·you have high blood pressure, heart disease, liver cirrhosis, or kidney disease ·you are taking a diuretic ·you have asthma

OTHER SAFETY INFORMATION

Other information store at controlled room temperature 20º-25ºC (68º-77ºF) read all product information before using.

use by expiration date on package

DOSAGE AND ADMINISTRATION

Directions do not use more than directed ·drink a full glass of water with each dose ·adults and children 12 years and over: take 2 caplets every 6 hours: not more than 8 caplets in 24 hours · children under 12 years of age: ask a doctor.

PREGNANCY AND BREAST FEEDING

Pregnancy/Breastfeeding ask a health professional before use.

It is especially important not to use aspirin during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery.

DO NOT USE

Do not use if you have ever had an allergic reaction to acetaminophen, aspirin or any other pain reliever/fever reducer ·with any other drug containing acetaminophen (prescription or nonprescription).If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist.

STOP USE

Stop use and ask doctor if an allergic reaction occurs.

Seek medical help right away.

you experience any of the following signs of stomach bleeding: · feel faint · vomit blood · have bloody or black stools ·have stomach pain that does not get better.

painful area is red or swollen any few symptoms appear ·ringing in the ears or loss of hearing occurs.

●pain gets worse or lasts for more than 10 days ● fever gets worse or lasts for more than 3 days

ACTIVE INGREDIENTS

Active ingredient(s) (in each caplet) Acetaminophen 250 mg Aspirin 250 mg (NSAID)* Caffeine 65 mg *nonsteroidal anti-inflammatory drug

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use if a prescription drug fordiabetes, gout, arthritis any other drug containing an NSAID (prescription or nonprescription) · a blood thinning (anticoagulant) or steroid drug ·any other drug, or are under a doctor’s care for any serious condition.

trandolapril 4 MG Oral Tablet

Generic Name: TRANDOLAPRIL

Brand Name: Trandolapril

Substance Name(s):
TRANDOLAPRIL

WARNINGS

Anaphylactoid and Possibly Related Reactions Presumably because angiotensin converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors, including trandolapril, may be subject to a variety of adverse reactions, some of them serious.

Anaphylactoid Reactions During Desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions.

In the same patients, these reactions did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered.

Anaphylactoid Reactions During Membrane Exposure Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.

Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

Head and Neck Angioedema In controlled trials ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients.

Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors including trandolapril.

Symptoms suggestive of angioedema or facial edema occurred in 0.13% of trandolapril-treated patients.

Two of the four cases were life-threatening and resolved without treatment or with medication (corticosteroids).

Angioedema associated with laryngeal edema can be fatal.

If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with trandolapril should be discontinued immediately, the patient treated in accordance with accepted medical care and carefully observed until the swelling disappears.

In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms.

Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, emergency therapy, including but not limited to subcutaneous epinephrine solution 1:1,000 (0.3 to 0.5 mL) should be promptly administered.

(See PRECAUTIONS – Information for Patients and ADVERSE REACTIONS .

) Patients receiving coadministration of an ACE inhibitor with an mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) or a neprilysin inhibitor (e.g., sacubitril) may be at increased risk for angioedema.

Intestinal Angioedema Intestinal angioedema has been reported in patients treated with ACE inhibitors.

These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.

The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor.

Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Hypotension Trandolapril can cause symptomatic hypotension.

Like other ACE inhibitors, trandolapril has only rarely been associated with symptomatic hypotension in uncomplicated hypertensive patients.

Symptomatic hypotension is most likely to occur in patients who have been salt- or volume-depleted as a result of prolonged treatment with diuretics, dietary salt restriction, dialysis, diarrhea, or vomiting.

Volume and/or salt depletion should be corrected before initiating treatment with trandolapril.

(See PRECAUTIONS – Drug Interactions and ADVERSE REACTIONS .) In controlled and uncontrolled studies, hypotension was reported as an adverse event in 0.6% of patients and led to discontinuations in 0.1% of patients.

In patients with concomitant congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia, and rarely, with acute renal failure and death.

In such patients, trandolapril therapy should be started at the recommended dose under close medical supervision.

These patients should be followed closely during the first 2 weeks of treatment and, thereafter, whenever the dosage of trandolapril or diuretic is increased.

(see DOSAGE AND ADMINISTRATION .

) Care in avoiding hypotension should also be taken in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease.

If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, normal saline may be administered intravenously.

A transient hypotensive response is not a contraindication to further doses; however, lower doses of trandolapril or reduced concomitant diuretic therapy should be considered.

Neutropenia/Agranulocytosis Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma.

Available data from clinical trials of trandolapril are insufficient to show that trandolapril does not cause agranulocytosis at similar rates.

As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen-vascular disease and/or renal disease should be considered.

Hepatic Failure ACE inhibitors rarely have been associated with a syndrome of cholestatic jaundice, fulminant hepatic necrosis, and death.

The mechanism of this syndrome is not understood.

Patients receiving ACE inhibitors who develop jaundice should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue trandolapril as soon as possible.

These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy.

Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

Perform serial ultrasound examinations to assess the intra-amniotic environment.

If oligohydramnios is observed, discontinue trandolapril, unless it is considered lifesaving for the mother.

Fetal testing may be appropriate, based on the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Closely observe infants with histories of in utero exposure to trandolapril for hypotension, oliguria, and hyperkalemia.

(See PRECAUTIONS, Pediatric Use .) Doses of 0.8 mg/kg/day (9.4 mg/m 2 /day) in rabbits, 1000 mg/kg/day (7000 mg/m 2 /day) in rats, and 25 mg/kg/day (295 mg/m 2 /day) in cynomolgus monkeys did not produce teratogenic effects.

These doses represent 10 and 3 times (rabbits), 1250 and 2564 times (rats), and 312 and 108 times (monkeys) the maximum projected human dose of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg woman.

DRUG INTERACTIONS

Drug Interactions Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.

Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy.

In general, avoid combined use of RAS inhibitors.

Closely monitor blood pressure, renal function and electrolytes in patients on trandolapril and other agents that affect the RAS.

Do not co-administer aliskiren with trandolapril in patients with diabetes.

Avoid use of aliskiren with trandolapril in patients with renal impairment (GFR <60 mL/min).

Concomitant Diuretic Therapy As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may experience an excessive reduction of blood pressure after initiation of therapy with trandolapril.

The possibility of exacerbation of hypotensive effects with trandolapril may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with trandolapril.

If it is not possible to discontinue the diuretic, the starting dose of trandolapril should be reduced.

(See DOSAGE AND ADMINISTRATION .

) Agents Increasing Serum Potassium Trandolapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone.

Use of potassium-sparing diuretics (spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes concomitantly with ACE inhibitors can increase the risk of hyperkalemia.

If concomitant use of such agents is indicated, they should be used with caution and with appropriate monitoring of serum potassium.

(See PRECAUTIONS .

) Antidiabetic Agents Concomitant use of ACE inhibitors and antidiabetic medicines (insulin or oral hypoglycemic agents) may cause an increased blood glucose lowering effect with greater risk of hypoglycemia.

Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy.

These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended.

If a diuretic is also used, the risk of lithium toxicity may be increased.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including trandolapril, may result in deterioration of renal function, including possible acute renal failure.

These effects are usually reversible.

Monitor renal function periodically in patients receiving trandolapril and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including trandolapril may be attenuated by NSAIDs.

Gold Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including trandolapril.

Mammalian Target of Rapamycin (mTOR) Inhibitors Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see Warnings – Head and Neck Angioedema).

Neprilysin Inhibitor Patients taking concomitant neprilysin inhibitors (e.g., sacubitril) may be at increased risk for angioedema (see WARNINGS ).

Other No clinically significant pharmacokinetic interaction has been found between trandolaprilat and food, cimetidine, digoxin, or furosemide.

The anticoagulant effect of warfarin was not significantly changed by trandolapril.

The hypotensive effect of certain inhalation anesthetics may be enhanced by ACE inhibitors including trandolapril.

(See PRECAUTIONS-Surgery/Anesthesia .

)

OVERDOSAGE

No data are available with respect to overdosage in humans.

The oral LD 50 of trandolapril in mice was 4875 mg/Kg in males and 3990 mg/Kg in females.

In rats, an oral dose of 5000 mg/Kg caused low mortality (1 male out of 5; 0 females).

In dogs, an oral dose of 1000 mg/Kg did not cause mortality and abnormal clinical signs were not observed.

In humans, the most likely clinical manifestation would be symptoms attributable to severe hypotension.

Symptoms also expected with ACE inhibitors are hypotension, hyperkalemia, and renal failure.

Laboratory determinations of serum levels of trandolapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of trandolapril overdose.

No data are available to suggest that physiological maneuvers (e.g., maneuvers to change the pH of the urine) might accelerate elimination of trandolapril and its metabolites.

Trandolaprilat is removed by hemodialysis.

Angiotensin II could presumably serve as a specific antagonist antidote in the setting of trandolapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities.

Because the hypotensive effect of trandolapril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat trandolapril overdose by infusion of normal saline solution.

DESCRIPTION

Trandolapril is the ethyl ester prodrug of a nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor, trandolaprilat.

Trandolapril is chemically described as (2S,3aR,7aS)-1-[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl] hexahydro-2-indolinecarboxylic acid, 1-ethyl ester.

Its molecular formula is C 24 H 34 N 2 O 5 and its structural formula is M.W.

= 430.54 Melting Point = 125°C Trandolapril USP is a white or almost white powder that is soluble (>100 mg/mL) in chloroform, dichloromethane, and methanol.

Trandolapril tablets USP contain 1 mg, 2 mg, or 4 mg of trandolapril USP for oral administration.

Each tablet also contains lactose monohydrate, corn starch, croscarmellose sodium, hypromellose, povidone, and sodium stearyl fumarate.

In addition 1 mg and 4 mg tablet also contains ferric oxide red and 2 mg tablet contains ferric oxide yellow.

Chemical Structure

HOW SUPPLIED

Trandolapril tablets USP are supplied as follows: Trandolapril Tablets USP 1 mg are salmon colored, round, biconvex, uncoated tablets debossed with ‘E’ on upper side of the bisector line on one side and ‘35’ on the other side.

Bottles of 100 NDC 57237-089-01 Trandolapril Tablets USP 2 mg are yellow colored, round, biconvex, uncoated tablets debossed with ‘E’ on one side and ‘36’ on the other side.

Bottles of 100 NDC 57237-090-01 Trandolapril Tablets USP 4 mg are rose colored, round, biconvex, uncoated tablets debossed with ‘E’ on one side and ‘37’ on the other side.

Bottles of 100 NDC 57237-091-01 Dispense in well-closed container with safety closure.

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

Distributed by: Rising Health, LLC Saddle Brook, NJ 07663 Made in India Code: TS/DRUGS/19/1993 Revised: 01/2018

GERIATRIC USE

Geriatric Use In placebo-controlled studies of trandolapril, 31.1% of patients were 60 years and older, 20.1% were 65 years and older, and 2.3% were 75 years and older.

No overall differences in effectiveness or safety were observed between these patients and younger patients.

(Greater sensitivity of some older individual patients cannot be ruled out.)

INDICATIONS AND USAGE

Hypertension Trandolapril tablets USP are indicated for the treatment of hypertension.

They may be used alone or in combination with other antihypertensive medication such as hydrochlorothiazide.

Heart Failure Post Myocardial Infarction or Left-Ventricular Dysfunction Post Myocardial Infarction Trandolapril tablets USP are indicated in stable patients who have evidence of left-ventricular systolic dysfunction (identified by wall motion abnormalities) or who are symptomatic from congestive heart failure within the first few days after sustaining acute myocardial infarction.

Administration of trandolapril to Caucasian patients has been shown to decrease the risk of death (principally cardiovascular death) and to decrease the risk of heart failure-related hospitalization (see CLINICAL PHARMACOLOGY -Heart Failure or Left-Ventricular Dysfunction Post Myocardial Infarction for details of the survival trial).

PEDIATRIC USE

Pediatric Use Neonates with a history of in utero exposure to trandolapril If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

The safety and effectiveness of trandolapril in pediatric patients have not been established.

NUSRING MOTHERS

Nursing Mothers Radiolabeled trandolapril or its metabolites are secreted in rat milk.

Trandolapril should not be administered to nursing mothers.

BOXED WARNING

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue trandolapril as soon as possible.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

(See WARNINGS: Fetal Toxicity .)

INFORMATION FOR PATIENTS

Information for Patients Angioedema Angioedema, including laryngeal edema, may occur at any time during treatment with ACE inhibitors, including trandolapril.

Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician.

(See WARNINGS and ADVERSE REACTIONS .

) Symptomatic Hypotension Patients should be cautioned that light-headedness can occur, especially during the first days of trandolapril therapy, and should be reported to a physician.

If actual syncope occurs, patients should be told to stop taking the drug until they have consulted with their physician.

(See WARNINGS .) All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting, resulting in reduced fluid volume, may precipitate an excessive fall in blood pressure with the same consequences of light-headedness and possible syncope.

Patients planning to undergo any surgery and/or anesthesia should be told to inform their physician that they are taking an ACE inhibitor that has a long duration of action.

Hyperkalemia Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician.

(See PRECAUTIONS .

) Neutropenia Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia.

Pregnancy Female patients of childbearing age should be told about the consequences of exposure to trandolapril during pregnancy.

Discuss treatment options with women planning to become pregnant.

Patients should be asked to report pregnancies to their physicians as soon as possible.

NOTE: As with many other drugs, certain advice to patients being treated with trandolapril is warranted.

This information is intended to aid in the safe and effective use of this medication.

It is not a disclosure of all possible adverse or intended effects.

DOSAGE AND ADMINISTRATION

Hypertension The recommended initial dosage of trandolapril tablets for patients not receiving a diuretic is 1 mg once daily in non-black patients and 2 mg in black patients.

Dosage should be adjusted according to the blood pressure response.

Generally, dosage adjustments should be made at intervals of at least 1 week.

Most patients have required dosages of 2 to 4 mg once daily.

There is little clinical experience with doses above 8 mg.

Patients inadequately treated with once-daily dosing at 4 mg may be treated with twice-daily dosing.

If blood pressure is not adequately controlled with trandolapril tablets monotherapy, a diuretic may be added.

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of trandolapril tablets.

To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with trandolapril tablets.

(See WARNINGS .

) Then, if blood pressure is not controlled with trandolapril tablets alone, diuretic therapy should be resumed.

If the diuretic cannot be discontinued, an initial dose of 0.5 mg trandolapril tablets should be used with careful medical supervision for several hours until blood pressure has stabilized.

The dosage should subsequently be titrated (as described above) to the optimal response.

(See WARNINGS , PRECAUTIONS and Drug Interactions .

) Concomitant administration of trandolapril tablets with potassium supplements, potassium salt substitutes, or potassium sparing diuretics can lead to increases of serum potassium.

(See PRECAUTIONS .

) Heart Failure Post Myocardial Infarction or Left-Ventricular Dysfunction Post Myocardial Infarction The recommended starting dose is 1 mg, once daily.

Following the initial dose, all patients should be titrated (as tolerated) toward a target dose of 4 mg, once daily.

If a 4 mg dose is not tolerated, patients can continue therapy with the greatest tolerated dose.

Dosage Adjustment in Renal Impairment or Hepatic Cirrhosis For patients with a creatinine clearance <30 mL/min.

or with hepatic cirrhosis, the recommended starting dose, based on clinical and pharmacokinetic data, is 0.5 mg daily.

Patients should subsequently have their dosage titrated (as described above) to the optimal response.

Zyrtec-D (cetirizine dihydrochloride 5 MG / pseudoephedrine hydrochloride 120 MG) 12 HR Extended Release Oral Tablet

Generic Name: CETIRIZINE HYDROCHLORIDE AND PSEUDOEPHEDRINE HYDROCHLORIDE

Brand Name: ZYRTEC-D Allergy Plus Congestion

Substance Name(s):
CETIRIZINE HYDROCHLORIDE
PSEUDOEPHEDRINE HYDROCHLORIDE

WARNINGS

Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine.

if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug.

If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.

Ask a doctor before use if you have heart disease thyroid disease diabetes glaucoma high blood pressure trouble urinating due to an enlarged prostate gland liver or kidney disease.

Your doctor should determine if you need a different dose.

Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives.

When using this product do not use more than directed drowsiness may occur avoid alcoholic drinks alcohol, sedatives, and tranquilizers may increase drowsiness be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if an allergic reaction to this product occurs.

Seek medical help right away.

you get nervous, dizzy, or sleepless symptoms do not improve within 7 days or are accompanied by fever If pregnant or breast-feeding: if breast-feeding: not recommended if pregnant: 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 due to hay fever or other upper respiratory allergies: runny nose sneezing itchy, watery eyes itching of the nose or throat nasal congestion reduces swelling of nasal passages temporarily relieves sinus congestion and pressure temporarily restores freer breathing through the nose

INACTIVE INGREDIENTS

Inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, titanium dioxide

PURPOSE

Active ingredients (in each extended release tablet) Purpose Cetirizine HCl 5 mg Antihistamine Pseudoephedrine HCl 120 mg Nasal decongestant

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 heart disease thyroid disease diabetes glaucoma high blood pressure trouble urinating due to an enlarged prostate gland liver or kidney disease.

Your doctor should determine if you need a different dose.

DOSAGE AND ADMINISTRATION

Directions do not break or chew tablet; swallow tablet whole adults and children 12 years and over take 1 tablet every 12 hours; do not take more than 2 tablets in 24 hours.

adults 65 years and over ask a doctor children under 12 years of age ask a doctor consumers with liver or kidney disease ask a doctor

PREGNANCY AND BREAST FEEDING

If pregnant or breast-feeding: if breast-feeding: not recommended if pregnant: ask a health professional before use.

DO NOT USE

Do not use if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine.

If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product.

STOP USE

Stop use and ask a doctor if an allergic reaction to this product occurs.

Seek medical help right away.

you get nervous, dizzy, or sleepless symptoms do not improve within 7 days or are accompanied by fever

ACTIVE INGREDIENTS

Active ingredients (in each extended release tablet) Purpose Cetirizine HCl 5 mg Antihistamine Pseudoephedrine HCl 120 mg Nasal decongestant

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives.

hyoscyamine sulfate 0.375 MG Biphasic 12 HR Extended Release Oral Tablet

Generic Name: HYOSCYAMINE SULFATE

Brand Name: Symax Duotab

Substance Name(s):
HYOSCYAMINE SULFATE

WARNINGS

Heat prostration can occur with drug use in the event of high environmental temperature.

Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy; in this instance, treatment would be inappropriate and possibly harmful.

This product may cause drowsiness or blurred vision.

Patients taking this product should be warned not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery or to perform hazardous tasks while taking this drug.

DRUG INTERACTIONS

Drug Interactions: Absorption of other oral medications may be decreased during concurrent use with anticholinergics due to decreased gastrointestinal motility and delayed gastric emptying.

Drug interactions may occur when anticholinergics are used with the following medications: antacids, antidiarrheals (adsorbent), other anticholinergics, antimyasthenics, cyclopropane, haloperidol, ketoconazole, metoclopramide, opioid (narcotic) analgesics, and potassium chloride.

OVERDOSAGE

The signs and symptoms of overdose are headache, nausea, vomiting, blurred vision, dilated pupils, hot dry skin, dizziness, dryness of the mouth, difficulty in swallowing and CNS stimulation.

Measures to be taken are immediate lavage of the stomach and injection of physostigmine 0.5 to 2 mg intravenously and repeated as necessary up to a total of 5 mg.

Fever may be treated symptomatically (tepid water sponge baths, hypothermic blanket).

Excitement to a degree which demands attention may be managed with sodium thiopental 2% solution given slowly intravenously or chloral hydrate (100-200 mL of a 2% solution) by rectal infusion.

In the event of progression of the curare-like effect to paralysis of the respiratory muscles, artificial respiration should be instituted and maintained until effective respiratory action returns.

In rats, the LD 50 for hyoscyamine is 375 mg/kg.

Hyoscyamine is dialyzable.

DESCRIPTION

Each purple and white, biphasic, capsule shaped tablet for oral administration is specially formulated to release 0.125 mg of hyoscyamine sulfate immediately and 0.250 mg hyoscyamine sulfate over the remaining 8 to 12 hours of the dosing period.

Hyoscyamine sulfate is one of the principal anticholinergic/antispasmodic components of belladonna alkaloids.

Hyoscyamine sulfate is Benzeneacetic acid, α-(hydroxymethyl)-, 8- methyl-8-azabicyclo[3.2.1]oct-3-yl ester, [3( S )- endo ]-, sulfate (2:1), dihydrate.

(C 17 H 23 NO 3 ) 2 • H 2 SO 4 • 2H 2 O M.W.

712.85 Hyoscyamine Sulfate

HOW SUPPLIED

Purple and white, bilayered, capsule-shaped tablets debossed “SYMAX” on one side, “DUOTAB” on the opposite side.

Bottles of 90 tablets NDC 64543-118-90, and professional physician starter packages of 1 tablet NDC 64543-118-02.

Storage and Handling Store at controlled room temperature, 20°-25°C (68°-77°F), see USP Controlled Room Temperature.

Dispense in tight, light-resistant containers as defined in the USP/NF.

KEEP THIS AND ALL MEDICATION OUT OF THE REACH OF CHILDREN.

IN CASE OF ACCIDENTAL OVERDOSE, SEEK PROFESSIONAL ASSISTANCE OR CONTACT A POISON CONTROL CENTER IMMEDIATELY.

Manufactured for: Capellon Pharmaceuticals, LLC Fort Worth, TX 76118 Rev.

05/2016 500157-03

GERIATRIC USE

Geriatric Use: Geriatric patients may respond to usual doses of anticholinergics with excitement, agitation, drowsiness, or confusion.

Geriatric patients are especially susceptible to the anticholinergic side effects, such as constipation, dryness of mouth, and urinary retention (especially in males).

If these side effects occur and continue or are severe, medication should probably be discontinued.

Caution is also recommended when anticholinergics are given to geriatric patients, because of the danger of precipitating undiagnosed glaucoma.

Memory may become severely impaired in geriatric patients, especially those who already have memory problems, with the continued use of anticholinergics since these drugs block the actions of acetylcholine, which is responsible for many functions of the brain, including memory functions.

INDICATIONS AND USAGE

This product may be used in functional intestinal disorders to reduce symptoms such as those seen in mild dysenteries and diverticulitis.

It can also be used to control gastric secretion, visceral spasm and hypermotility in cystitis, pylorospasm and associated abdominal cramps.

Along with appropriate analgesics, this product is indicated in symptomatic relief of biliary and renal colic and as a drying agent in the relief of symptoms of acute rhinitis.

This product is effective as adjunctive therapy in the treatment of peptic ulcer and irritable bowel syndrome, acute enterocolitis and other functional gastrointestinal disorders.

PEDIATRIC USE

Pediatric Use: This product is not recommended for use in children under twelve years of age.

Infants and young children are especially susceptible to the toxic effects of anticholinergics.

Close supervision is recommended for infants and children with spastic paralysis or brain damage since an increased response to anticholinergics has been reported in these patients and dosage adjustments are often required.

When anticholinergics are given to children where the environmental temperature is high, there is a risk of a rapid increase in body temperature because of these medications’ suppression of sweat gland activity.

A paradoxical reaction characterized by hyperexcitability may occur in children taking large doses of anticholinergics.

PREGNANCY

Pregnancy: Pregnancy Category C.

Animal reproduction studies have not been conducted with this product.

It is also not known whether this product can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Hyoscyamine crosses the placenta.

This product should be given to a pregnant woman only if clearly needed.

NUSRING MOTHERS

Nursing Mothers: This product is excreted in human milk.

This product should not be administered to a nursing mother.

INFORMATION FOR PATIENTS

Information for Patients: This medication should be taken 30 minutes to one hour before meals.

Tablets should be swallowed whole.

This medication should be used with caution during exercise or hot weather; overheating may result in heat stroke.

Hyoscyamine may cause drowsiness, dizziness or blurred vision; patients should observe caution before driving, using machinery or performing other tasks requiring mental alertness.

INACTIVE INGREDIENTS

Inactive ingredients include calcium phosphate, D&C Red #30, FD&C Blue #1, lactose monohydrate, magnesium stearate, methylcellulose, povidone, silicified microcrystalline cellulose, and sodium starch glycolate.

DOSAGE AND ADMINISTRATION

Adults and children 12 years of age and older: 1 to 2 tablets every 12 hours.

Dosage may be adjusted to 1 tablet every 8 hours if needed.

Do not exceed 4 tablets in 24 hours.

Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.

Tablets should be swallowed whole.