Drug Intercation

Generic Name: MIDAZOLAM HYDROCHLORIDE

Brand Name: Midazolam Hydrochloride

Substance Name(s):
MIDAZOLAM HYDROCHLORIDE

WARNINGS

Personnel and Equipment for Monitoring and Resuscitation Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that are equipped to provide continuous monitoring of respiratory and cardiac function.

Midazolam HCl syrup must only be administered to patients if they will be monitored by direct visual observation by a health care professional.

If midazolam HCl syrup will be administered in combination with other anesthetic drugs or drugs which depress the central nervous system, patients must be monitored by persons specifically trained in the use of these drugs and, in particular, in the management of respiratory effects of these drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

For deeply sedated patients, a dedicated individual whose sole responsibility is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Patients should be continuously monitored for early signs of hypoventilation, airway obstruction, or apnea with means for detection readily available (eg, pulse oximetry).

Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately.

The immediate availability of specific reversal agents (flumazenil) is highly recommended.

Vital signs should continue to be monitored during the recovery period.

Because midazolam can depress respiration [see CLINICAL PHARMACOLOGY] , especially when used concomitantly with opioid agonists and other sedatives [see DOSAGE AND ADMINISTRATION] , it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been occasionally reported following premedication (sedation prior to induction of anesthesia) with oral midazolam; such events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease.

Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation, respiratory depression, coma and death.

If a decision is made to use midazolam concomitantly with opioids, monitor patients for respiratory depression and sedation [see PRECAUTIONS/Drug Interactions] .

Risk of Respiratory Adverse Events Serious respiratory adverse events have occurred after administration of oral midazolam, most often when midazolam was used in combination with other central nervous system depressants.

These adverse events have included respiratory depression, airway obstruction, oxygen desaturation, apnea, and rarely, respiratory and/or cardiac arrest [see BOX WARNING] .

When oral midazolam is administered as the sole agent at recommended doses respiratory depression, airway obstruction, oxygen desaturation, and apnea occur infrequently [see DOSAGE AND ADMINISTRATION] .

Prior to the administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured.

Individualization of Dosage Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing central nervous system depression.

See DOSAGE AND ADMINISTRATION for complete information.

Other Adverse Events Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients.

Consideration should be given to the possibility of paradoxical reaction.

Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding.

Reversal of such responses with flumazenil has been reported in pediatric and adult patients.

Concomitant Use of Central Nervous System Depressants Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

Drug-Drug Interactions Coadministration of oral midazolam in patients who are taking ketoconazole and intraconazole, and saquinavir has been shown to result in large increases in Cmax and AUC of midazolam due to a decrease in plasma clearance of midazolam [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions and PRECAUTIONS] .

Due to the potential for intense and prolonged sedation and respiratory depression, midazolam syrup should only be coadministered with these medications if absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency.

Debilitation and Comorbidity Considerations Higher risk pediatric surgical patients may require lower doses, whether or not concomitant sedating medications have been administered.

Pediatric patients with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effect of midazolam.

Pediatric patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction.

Patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly [see CLINICAL PHARMACOLOGY] .

Return to Cognitive Function Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

Gross tests of recovery from the effects of midazolam HCl syrup [see CLINICAL PHARMACOLOGY] cannot be relied upon to predict reaction time under stress.

It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer.

Particular care should be taken to assure safe ambulation.

Neonatal Sedation and Withdrawal Syndrome Use of midazolam HCl syrup 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 midazolam HCl syrup during pregnancy or labor for signs of sedation and monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal; manage these infants accordingly.

Usage in Preterm Infants and Neonates Midazolam HCl syrup has not been studied in patients less than 6 months of age.

Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear.

However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see PRECAUTIONS; Pregnancy, Pediatric Use and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children and pregnant women needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.

Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

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.

Monitor patients closely for respiratory depression and sedation.

Other CNS Depressants One case was reported of inadequate sedation with chloral hydrate and later with oral midazolam due to a possible interaction with methylphenidate administered chronically in a 2-year-old boy with a history of Williams syndrome.

The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate.

The sedative effect of midazolam HCl syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol.

Consequently, the dose of midazolam HCl syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see DOSAGE AND ADMINISTRATION] .

No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.

Inhibitors of CYP3A4 Isozymes Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics).

Drugs such as diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil were shown to significantly increase the C max and AUC of orally administered midazolam.

These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam.

Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam.

Caution is advised when midazolam HCl syrup is used concomitantly with these drugs.

Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions] .

Inducers of CYP3A4 Isozymes Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and cause a markedly decreased C max and AUC of oral midazolam in adult studies.

Although clinical studies have not been performed, phenobarbital is expected to have the same effect.

Caution is advised when administering midazolam HCl syrup to patients receiving these medications and if necessary dose adjustments should be considered.

OVERDOSAGE

Clinical Presentation 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: Dependence and Withdrawal Reactions).

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.

Management of Overdose In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management.

Flumazenil, a specific benzodiazepine receptor antagonist, is 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 longterm 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 (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.

DESCRIPTION

Midazolam is a benzodiazepine available as midazolam HCl syrup for oral administration.

Midazolam, a white to light yellow crystalline compound, is insoluble in water, but can be solubilized in aqueous solutions by formation of the hydrochloride salt in situ under acidic conditions.

Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 H -imidazo[1,5-a][1,4]benzodiazepine hydrochloride.

Midazolam hydrochloride has the molecular formula C 18 H 13 ClFN 3 ·HCl, a calculated molecular weight of 362.25 and the following structural formula: Each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg midazolam compounded with artificial bitterness modifier, citric acid anhydrous, D&C Red #33, edetate disodium, glycerin, mixed fruit flavor, sodium benzoate, sodium citrate, sorbitol, and water; the pH is adjusted to 2.8 to 3.6 with hydrochloric acid.

Under the acidic conditions required to solubilize midazolam in the syrup, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring.

The amount of open-ring form is dependent upon the pH of the solution.

At the specified pH of the syrup, the solution may contain up to about 40% of the open-ring compound.

At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such.

The following chart below plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions.

As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 2.8 to 3.6.

Above pH 5, at least 99% of the mixture is present in the closed-ring form.

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HOW SUPPLIED

Midazolam HCl Syrup is supplied as a clear, red to purplish-red, mixed fruit flavored syrup containing midazolam hydrochloride equivalent to 2 mg of midazolam/mL; each amber glass bottle of 118 mL of syrup is supplied with 1 press-in bottle adapter, 4 single-use, graduated, oral dispensers and 4 tip caps; 10 x bottle of 2.5 mL is supplied with 10 single-use, graduated, oral dispensers and 10 tip caps.

NDC 0574-0150-04 Bottle of 118 mL.

NDC 0574-0150-25 10 x Bottle of 2.5 mL.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.]

GERIATRIC USE

Geriatric Use The safety and efficacy of this product have not been fully studied in geriatric patients.

Therefore, there are no available data on a safe dosing regimen.

One study in geriatric subjects, using midazolam 7.5 mg as a premedicant prior to general anesthesia, noted a 60% incidence of hypoxemia (pO 2 <90% for over 30 seconds) at sometime during the operative procedure versus 15% for the nonpremedicated group.

Until further information is available it is recommended that this product should not be used in geriatric patients.

Use in Patients With Heart Disease Following oral administration of 7.5 mg of midazolam to adult patients with congestive heart failure, the half-life of midazolam was 43% higher than in control subjects.

One study suggests that hypercarbia or hypoxia following premedication with oral midazolam might pose a risk to children with congenital heart disease and pulmonary hypertension, although there are no known reports of pulmonary hypertensive crisis that had been triggered by premedication.

In the study, 22 children were premedicated with oral midazolam (0.75 mg/kg) or IM morphine plus scopolamine prior to elective repair of congenital cardiac defects.

Both premedication regimens increased PtcCO 2 and decreased SpO 2 and respiratory rates preferentially in patients with pulmonary hypertension.

INDICATIONS AND USAGE

Midazolam HCl syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

Midazolam HCl syrup is intended for use in monitored settings only and not for chronic or home use [see WARNINGS] .

PEDIATRIC USE

Pediatric Use Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam Hydrochloride Syrup 2 mg/mL, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data.

[See WARNINGS; Pediatric Neurotoxicity, PRECAUTIONS; Pregnancy, and Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

PREGNANCY

Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including midazolam HCl syrup, during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

Risk Summary Infants 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 and 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 ).

The 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 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 midazolam HCl syrup during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.

Monitor neonates exposed to midazolam HCl syrup 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 Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

All doses produced slight to moderate ataxia.

The high dose produced a 5% decrease in maternal body weight gain compared to control.

Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity.

Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21).

All doses produced ataxia.

The high dose produced a slight decrease in maternal body weight gain compared to control.

There were no clear adverse effects noted in the offspring.

The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits ( see WARNINGS, Pediatric Neurotoxicity, PRECAUTIONS, Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY ).

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

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

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

A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.

BOXED WARNING

WARNINGS Personnel and Equipment for Monitoring and Depression Midazolam HCl syrup has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings.

Midazolam HCl syrup has been associated with reports of respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used concomitantly with other central nervous system depressants.

Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Risks From Concomitant Use With Opioids Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

Monitor patients for respiratory depression and sedation [see WARNINGS, PRECAUTIONS/Drug Interactions] .

INFORMATION FOR PATIENTS

Information for Patients To assure safe and effective use of midazolam HCl syrup, the following information and instructions should be communicated to the patient when appropriate: 1.

Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication, antibiotics, and protease inhibitors, including drugs you buy without a prescription.

Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment.

Inform your physician if you are pregnant or are planning to become pregnant.

Inform your physician if you are nursing.

Patients should be informed of the pharmacological effects of midazolam HCl syrup, such as sedation and amnesia, which in some patients may be profound.

Midazolam HCl syrup should not be taken in conjunction with grapefruit juice.

For pediatric patients, particular care should be taken to assure safe ambulation.

Effect of Anesthetic and Sedation Drugs on Early Brain Development: Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains.

Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Pregnancy Advise pregnant females that use of midazolam HCl syrup 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.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to midazolam HCl syrup during pregnancy (see Precautions, Pregnancy ).

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

Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs.

A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant (see Precautions, Nursing Mothers ).

DOSAGE AND ADMINISTRATION

Midazolam HCl syrup is indicated for use as a single dose (0.25 to 1.0 mg/kg with a maximum dose of 20 mg) for preprocedural sedation and anxiolysis in pediatric patients.

Midazolam HCl syrup is not intended for chronic administration.

Monitoring Midazolam HCl syrup should only be used in hospital or ambulatory care settings, including physicians’ and dentists’ offices that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual whose sole responsibility it is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Continuous monitoring of respiratory and cardiac function is required.

Midazolam HCl syrup must be given only to patients if they will be monitored by direct visual observation by a health care professional.

Midazolam HCl syrup should only be administered by persons specifically trained in the use of anesthetic drugs and the management of respiratory effects of anesthetic drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

Patient response to sedative agents, and resultant respiratory status, is variable.

Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes, particularly when coadministered with anesthetic agents, other CNS depressants, and concomitant medications which may potentially cause a more intense and prolonged sedation [see PRECAUTIONS: Drug Interactions] .

This is especially true in pediatric patients.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities.

Further recommendations include appropriate presedation fasting.

Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing CNS depression.

Younger (<6 years of age) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring.

When midazolam HCl syrup is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased.

For appropriate patient monitoring, see WARNINGS and : Monitoring.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

The recommended dose for pediatric patients is a single dose of 0.25 to 0.5 mg/kg, depending on the status of the patient and desired effect, up to a maximum dose of 20 mg.

In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitant medications, and medical need [see WARNINGS and PRECAUTIONS] .

The younger (6 months to <6 years of age) and less cooperative patients may require a higher than usual dose up to 1.0 mg/kg.

A dose of 0.25 mg/kg may suffice for older (6 to <16 years of age) or cooperative patients, especially if the anticipated intensity and duration of sedation is less critical.

For all pediatric patients, a dose of 0.25 mg/kg should be considered when midazolam HCl syrup is administered to patients with cardiac or respiratory compromise, other higher risk surgical patients, and patients who have received concomitant narcotics or other CNS depressants.

As with any potential respiratory depressant, these patients must be monitored for signs of cardiorespiratory depression after receiving midazolam HCl syrup.

In obese pediatric patients, the dose should be calculated based on ideal body weight.

Midazolam HCl syrup has not been studied, nor is it intended for chronic use.

USE OF ORAL DISPENSERS AND PIBA 1.

Remove the cap.

Before inserting the tip of the oral dispenser into bottle adapter, push the plunger completely down toward the tip of the oral dispenser.

Insert tip firmly into opening of the bottle adapter.

Turn the entire unit (bottle and oral dispenser) upside down.

Pull the plunger out slowly until the desired amount of medication is withdrawn into the oral dispenser.

Turn the entire unit right side up and remove the oral dispenser slowly from the bottle.

The tip of the dispenser may be covered with a tip cap, until time of use.

Close bottle with cap after each use.

Dispense directly into mouth.

Do not mix with any liquid (such as grapefruit juice) prior to dispensing.

INSERTION OF PRESS-IN BOTTLE ADAPTER (PIBA) 1.

Remove the cap and push bottle adapter into neck of bottle.

Close the bottle tightly with cap.

This will assure the proper seating of the bottle adapter in the bottle.

DISPOSAL OF MIDAZOLAM HCl SYRUP The disposal of Schedule IV controlled substances must be consistent with State and Federal Regulations.

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WARNINGS

Hepatic Effects SPORANOX ® has been associated with rare cases of serious hepatotoxicity, including liver failure and death.

Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment.

If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed.

Continued SPORANOX ® use or reinstitution of treatment with SPORANOX ® is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk.

(See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS .) Cardiac Dysrhythmias Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with SPORANOX ® and/or other CYP3A4 inhibitors.

Concomitant administration of these drugs with SPORANOX ® is contraindicated.

(See BOXED WARNING , CONTRAINDICATIONS , and PRECAUTIONS: Drug Interactions .) Cardiac Disease SPORANOX ® Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.

SPORANOX ® Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.

For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX ® therapy.

These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders.

Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment.

If signs or symptoms of CHF appear during administration of SPORANOX ® Capsules, discontinue administration.

Itraconazole has been shown to have a negative inotropic effect.

When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented.

In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.

SPORANOX ® has been associated with reports of congestive heart failure.

In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses.

Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole.

In addition, itraconazole can inhibit the metabolism of calcium channel blockers.

Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF.

Concomitant administration of SPORANOX ® and felodipine or nisoldipine is contraindicated.

Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections.

(See CLINICAL PHARMACOLOGY: Special Populations , CONTRAINDICATIONS , PRECAUTIONS: Drug Interactions , and ADVERSE REACTIONS: Post-marketing Experience for more information.) Interaction potential SPORANOX ® has a potential for clinically important drug interactions.

Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death.

Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS: Drug Interactions.

Interchangeability SPORANOX ® (itraconazole) Capsules and SPORANOX ® Oral Solution should not be used interchangeably.

This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given.

In addition, the topical effects of mucosal exposure may be different between the two formulations.

Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

DRUG INTERACTIONS

Drug Interactions Effect of SPORANOX ® on Other Drugs Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors.

Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP).

Consequently, SPORANOX ® has the potential to interact with many concomitant drugs resulting in either increased or sometimes decreased concentrations of the concomitant drugs.

Increased concentrations may increase the risk of adverse reactions associated with the concomitant drug which can be severe or life-threatening in some cases (e.g., QT prolongation, Torsade de Pointes , respiratory depression, hepatic adverse reactions, hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism).

Reduced concentrations of concomitant drugs may reduce their efficacy.

Table 1 lists examples of drugs that may have their concentrations affected by itraconazole, but is not a comprehensive list.

Refer to the approved product labeling to become familiar with the interaction pathways, risk potential, and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX ® .

Although many of the clinical drug interactions in Table 1 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX ® .

Table 1 Drug Interactions with SPORANOX ® that Affect Concomitant Drug Concentrations Concomitant Drug Within Class Prevention or Management Drug Interactions with SPORANOX ® that Increase Concomitant Drug Concentrations and May Increase Risk of Adverse Reactions Associated with the Concomitant Drug Alpha Blockers Alfuzosin Silodosin Tamsulosin Not recommended during and 2 weeks after SPORANOX ® treatment.

Analgesics Methadone Contraindicated during and 2 weeks after SPORANOX ® treatment.

Fentanyl Not recommended during and 2 weeks after SPORANOX ® treatment.

Alfentanil Buprenorphine (IV and sublingual) Oxycodone Based on clinical drug interaction information with itraconazole.

Sufentanil Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antiarrhythmics Disopyramide Dofetilide Dronedarone Quinidine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Digoxin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antibacterials Bedaquiline Based on 400 mg Bedaquiline once daily for 2 weeks.

Concomitant SPORANOX ® not recommended for more than 2 weeks at any time during bedaquiline treatment.

Rifabutin Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 2 .

Clarithromycin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

See also Table 2 .

Trimetrexate Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Anticoagulants and Antiplatelets Ticagrelor Contraindicated during and 2 weeks after SPORANOX ® treatment.

Apixaban Rivaroxaban Vorapaxar Not recommended during and 2 weeks after SPORANOX ® treatment.

Cilostazol Dabigatran Warfarin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Anticonvulsants Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 2 .

Antidiabetic Drugs Repaglinide Saxagliptin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antihelminthics, Antifungals and Antiprotozoals Isavuconazonium Contraindicated during and 2 weeks after SPORANOX ® treatment.

Praziquantel Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Artemether-lumefantrine Quinine Monitor for adverse reactions.

Antimigraine Drugs Ergot alkaloids (e.g., dihydroergotamine, ergotamine) Contraindicated during and 2 weeks after SPORANOX ® treatment.

Eletriptan Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary Antineoplastics Irinotecan Contraindicated during and 2 weeks after SPORANOX ® treatment.

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-emtansine Vinca alkaloids Not recommended during and 2 weeks after SPORANOX ® treatment.

Bortezomib Brentuximab-vedotin Busulfan Erlotinib Gefitinib Idelalisib Imatinib Ixabepilone Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Vandetanib Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For idelalisib, see also Table 2 .

Antipsychotics, Anxiolytics and Hypnotics Alprazolam Aripiprazole Buspirone Diazepam Haloperidol Midazolam (IV) Quetiapine Ramelteon Risperidone Suvorexant Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Zopiclone Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Lurasidone Midazolam (oral) Pimozide Triazolam Contraindicated during and 2 weeks after SPORANOX ® treatment.

Antivirals Simeprevir Not recommended during and 2 weeks after SPORANOX ® treatment.

Daclatasvir Indinavir Maraviroc Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For indinavir, see also Table 2 .

Cobicistat Elvitegravir (ritonavir-boosted) Ritonavir Saquinavir (unboosted) Monitor for adverse reactions.

See also Table 2 .

Tenofovir disoproxil fumarate Monitor for adverse reactions.

Beta Blockers Nadolol Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Calcium Channel Blockers Felodipine Nisoldipine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Diltiazem Other dihydropyridines Verapamil Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For diltiazem, see also Table 2 .

Cardiovascular Drugs, Miscellaneous Ivabradine Ranolazine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Aliskiren Riociguat Sildenafil (for pulmonary hypertension) Tadalafil (for pulmonary hypertension) Not recommended during and 2 weeks after SPORANOX ® treatment.

For sildenafil and tadalafil, see also Urologic Drugs below.

Bosentan Guanfacine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Contraceptives Dienogest Ulipristal Monitor for adverse reactions.

Diuretics Eplerenone Contraindicated during and 2 weeks after SPORANOX ® treatment.

Gastrointestinal Drugs Cisapride Naloxegol Contraindicated during and 2 weeks after SPORANOX ® treatment.

Aprepitant Loperamide Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Netupitant Monitor for adverse reactions.

Immunosuppressants Everolimus Sirolimus Temsirolimus (IV) Not recommended during and 2 weeks after SPORANOX ® treatment.

Budesonide (inhalation) Budesonide (non-inhalation) Ciclesonide (inhalation) Cyclosporine (IV) Cyclosporine (non-IV) Dexamethasone Fluticasone (inhalation) Fluticasone (nasal) Methylprednisolone Tacrolimus (IV) Tacrolimus (oral) Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Lipid-Lowering Drugs Lomitapide Lovastatin Simvastatin Contraindicated during and 2 weeks after SPORANOX ® treatment.

Atorvastatin Monitor for drug adverse reactions.

Concomitant drug dose reduction may be necessary .

Respiratory Drugs Salmeterol Not recommended during and 2 weeks after SPORANOX ® treatment.

SSRIs, Tricyclics and Related Antidepressants Venlafaxine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Urologic Drugs Avanafil Contraindicated during and 2 weeks after SPORANOX ® treatment.

Fesoterodine Patients with moderate to severe renal or hepatic impairment : Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Solifenacin Patients with severe renal or moderate to severe hepatic impairment : Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Darifenacin Vardenafil Not recommended during and 2 weeks after SPORANOX ® treatment.

Dutasteride Oxybutynin Sildenafil (for erectile dysfunction) Tadalafil (for erectile dysfunction and benign prostatic hyperplasia) Tolterodine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For sildenafil and tadalafil, see also Cardiovascular Drugs above.

Miscellaneous Drugs and Other Substances Colchicine Patients with renal or hepatic impairment: Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Not recommended during and 2 weeks after SPORANOX ® treatment.

Eliglustat CYP2D6 EMs EMs: extensive metabolizers; IMs: intermediate metabolizers, PMs: poor metabolizers taking a strong or moderate CYP2D6 inhibitor, CYP2D6 IMs , or CYP2D6 PMs : Contraindicated during and 2 weeks after SPORANOX ® treatment.

CYP2D6 EMs not taking a strong or moderate CYP2D6 inhibitor : Monitor for adverse reactions.

Eliglustat dose reduction may be necessary.

Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

Alitretinoin (oral) Cabergoline Cannabinoids Cinacalcet Ivacaftor Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Vasopressin Receptor Antagonists Conivaptan Tolvaptan Not recommended during and 2 weeks after SPORANOX ® treatment.

Drug Interactions with SPORANOX ® that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant Drug Antineoplastics Regorafenib Not recommended during and 2 weeks after SPORANOX ® treatment.

Gastrointestinal Drugs Saccharomyces boulardii Not recommended during and 2 weeks after SPORANOX ® treatment.

Nonsteroidal Anti-Inflammatory Drugs Meloxicam Concomitant drug dose increase may be necessary.

Effect of Other Drugs on SPORANOX ® Itraconazole is mainly metabolized through CYP3A4.

Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole.

Some concomitant drugs have the potential to interact with SPORANOX ® resulting in either increased or sometimes decreased concentrations of SPORANOX ® .

Increased concentrations may increase the risk of adverse reactions associated with SPORANOX ® .

Decreased concentrations may reduce SPORANOX ® efficacy.

Table 2 lists examples of drugs that may affect itraconazole concentrations, but is not a comprehensive list.

Refer to the approved product labeling to become familiar with the interaction pathways, risk potential and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX ® .

Although many of the clinical drug interactions in Table 2 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX ® .

Table 2.

Drug Interactions with Other Drugs that Affect SPORANOX ® Concentrations Concomitant Drug Within Class Prevention or Management Drug Interactions with Other Drugs that Increase SPORANOX ® Concentrations and May Increase Risk of Adverse Reactions Associated with SPORANOX ® Antibacterials Ciprofloxacin Based on clinical drug interaction information with itraconazole.

Erythromycin Clarithromycin Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

Antineoplastics Idelalisib Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

See also Table 1 .

Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavir Ritonavir Saquinavir Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

For, cobicistat, elvitegravir, indinavir, ritonavir, and saquinavir, see also Table 1 .

Calcium Channel Blockers Diltiazem Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

See also Table 1 .

Drug Interactions with Other Drugs that Decrease SPORANOX ® Concentrations and May Reduce Efficacy of SPORANOX ® Antibacterials Isoniazid Rifampicin Not recommended 2 weeks before and during SPORANOX ® treatment.

Rifabutin Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 1 .

Anticonvulsants Phenobarbital Phenytoin Not recommended 2 weeks before and during SPORANOX ® treatment.

Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 1 .

Antivirals Efavirenz Nevirapine Not recommended 2 weeks before and during SPORANOX ® treatment.

Gastrointestinal Drugs Drugs that reduce gastric acidity e.g.

acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H 2 – receptor antagonists and proton pump inhibitors.

Use with caution.

Administer acid neutralizing medicines at least 2 hours before or 2 hours after the intake of SPORANOX ® capsules Miscellaneous Drugs and Other Substances Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

Pediatric Population Interaction studies have only been performed in adults.

OVERDOSAGE

Itraconazole is not removed by dialysis.

In the event of accidental overdosage, supportive measures should be employed.

Contact a certified poison control center for the most up to date information on the management of SPORANOX ® Capsules overdosage (1-800-222-1222 or www.poison.org).

In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this package insert for itraconazole.

(See ADVERSE REACTIONS .)

DESCRIPTION

SPORANOX ® is the brand name for itraconazole, an azole antifungal agent.

Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers.

It may be represented by the following structural formula and nomenclature: (±)-1-[( R *)- sec -butyl]-4-[ p -[4-[ p -[[(2 R *,4 S *)-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one mixture with (±)-1-[( R *)- sec -butyl]-4-[ p -[4-[ p -[[(2 S *,4 R *)-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one or (±)-1-[( RS )- sec -butyl]-4-[ p -[4-[ p -[[(2 R ,4 S )-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one Itraconazole has a molecular formula of C 35 H 38 Cl 2 N 8 O 4 and a molecular weight of 705.64.

It is a white to slightly yellowish powder.

It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane.

It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1.

SPORANOX ® Capsules contain 100 mg of itraconazole coated on sugar spheres (composed of sucrose, maize starch, and purified water).

Inactive ingredients are hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, titanium dioxide, FD&C Blue No.

1, FD&C Blue No.

2, D&C Red No.

22 and D&C Red No.

28.

Chemical Structure

CLINICAL STUDIES

Description of Clinical Studies Blastomycosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status.

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.

Histoplasmosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients).

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases.

Histoplasmosis in HIV-infected patients Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients.

The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.

Aspergillosis Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S.

for patients who either failed or were intolerant of amphotericin B therapy (N=190).

The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population.

Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months.

Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.

Onychomycosis of the toenail Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX ® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX ® Capsules once daily for 12 consecutive weeks.

Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients.

Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity).

The mean time to overall success was approximately 10 months.

Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).

Onychomycosis of the fingernail Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX ® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX ® Capsules b.i.d., followed by a 3-week period without SPORANOX ® , which was followed by a second 1-week pulse of 200 mg of SPORANOX ® Capsules b.i.d.

Results demonstrated mycologic cure in 61% of patients.

Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure.

The mean time to overall success was approximately 5 months.

None of the patients who achieved overall success relapsed.

HOW SUPPLIED

Product: 63629-1647

GERIATRIC USE

Geriatric Use Clinical studies of SPORANOX ® Capsules did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

It is advised to use SPORANOX ® Capsules in these patients only if it is determined that the potential benefit outweighs the potential risks.

In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole.

Several of these reports included concurrent administration of quinidine which is contraindicated (See BOXED WARNING: Drug Interactions , CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions ).

MECHANISM OF ACTION

Mechanism of Action In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

INDICATIONS AND USAGE

SPORANOX ® (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: Blastomycosis, pulmonary and extrapulmonary Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.

Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms.

Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly.

SPORANOX ® Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and Onychomycosis of the fingernail due to dermatophytes (tinea unguium).

Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.

(See CLINICAL PHARMACOLOGY: Special Populations , CONTRAINDICATIONS , WARNINGS , and ADVERSE REACTIONS: Post-marketing Experience for more information.) Description of Clinical Studies Blastomycosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status.