Suprane

Dosage Froms And Strengths

SUPRANE (desflurane, USP) is a colorless, non-flammable, volatile liquid (below 22.8°C) for inhalation, 100% desflurane.

Storage And Handling

SUPRANE (desflurane, USP) is available in an amber-colored glass bottle or an aluminum bottle containing 240 mL of desflurane as follows:

Safety And Handling

Occupational Caution

There is no specific work exposure limit established for SUPRANE. However, the National Institute for Occupational Safety and Health Administration (NIOSH) recommends that no worker should be exposed at ceiling concentrations greater than 2 ppm of any halogenated anesthetic agent over a sampling period not to exceed one hour.

Principle routes of exposure include:

Skin contact

May cause skin irritation. In case of contact, immediately flush skin with plenty of water. Remove contaminated clothing and shoes. Seek medical attention if irritation develops.

Eye contact

May cause eye irritation. In case of contact, immediately flush eyes with plenty of water for at least 15 minutes. Seek medical attention if irritation develops.

Ingestion

No specific hazards other than therapeutic effects. Do NOT induce vomiting unless directed to do so by medical personnel. Never give anything by mouth to an unconscious person. If large quantities of this material are swallowed, seek medical attention immediately.

Inhalation

If individuals smell vapors, or experience dizziness or headaches, they should be moved to an area with fresh air. Individuals could also experience the following: Cardiovascular effects: may include fluctuations in heart rate, changes in blood pressure, chest pain. Respiratory effects: may include shortness of breath, bronchospasms, laryngospasms, respiratory depression. Gastrointestinal effects: may include nausea, upset stomach, loss of appetite. Nervous System effects: may include ataxia, tremor, disturbance of speech, lethargy, headache, dizziness, blurred vision.

The predicted effects of acute overexposure by inhalation of SUPRANE include headache, dizziness or (in extreme cases) unconsciousness.

There are no documented adverse effects of chronic exposure to halogenated anesthetic vapors (Waste Anesthetic Gases or WAGs) in the workplace. Although results of some epidemiological studies suggest a link between exposure to halogenated anesthetics and increased health problems (particularly spontaneous abortion), the relationship is not conclusive. Since exposure to WAGs is one possible factor in the findings for these studies, operating room personnel, and pregnant women in particular, should minimize exposure. Precautions include adequate general ventilation in the operating room, the use of a well-designed and well-maintained scavenging system; work practices to minimize leaks and spills while the anesthetic agent is in use, and routine equipment maintenance to minimize leaks.

Consistent with clinical data, concentrations would need to reach 2-3% in inspired air before individuals would likely experience dizziness or other physiologic effects.

Storage

Store at room temperature, 15°-30°C (59°-86°F). SUPRANE has been demonstrated to be stable for the period defined by the expiration dating on the label. The bottle should be recapped after each use of SUPRANE.

Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 USA. Revised: April 2017

Induction Of Anesthesia

SUPRANE is indicated as an inhalation agent for induction of anesthesia for inpatient and outpatient surgery in adults.

SUPRANE is contraindicated as an inhalation agent for the induction of anesthesia in pediatric patients because of a high incidence of moderate to severe upper airway adverse events.

Maintenance Of Anesthesia

SUPRANE is indicated as an inhalation agent for maintenance of anesthesia for inpatient and outpatient surgery in adults and in pediatric patients.

After induction of anesthesia with agents other than SUPRANE, and tracheal intubation, SUPRANE is indicated for maintenance of anesthesia in infants and children.

SUPRANE is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm, and secretions.

Only persons trained in the administration of general anesthesia should administer SUPRANE. Only a vaporizer specifically designed and designated for use with desflurane should be utilized for its administration. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available.

SUPRANE is administered by inhalation. The administration of general anesthesia must be individualized based on the patient’s response. Hypotension and respiratory depression increase as anesthesia with SUPRANE is deepened. The minimum alveolar concentration (MAC) of SUPRANE decreases with increasing patient age. The MAC for SUPRANE is also reduced by concomitant N₂O administration (see Table 1). The dose should be adjusted accordingly. The following table provides mean relative potency based upon age and effect of N₂O in predominately ASA physical status I or II patients.

Benzodiazepines and opioids decrease the MAC of SUPRANE. SUPRANE also decreases the doses of neuromuscular blocking agents required. The dose should be adjusted accordingly.

Table 1 Effect of Age on Minimum Alveolar Concentration of Desflurane Mean ± SD (percent atmospheres)

Preanesthetic Medication

Issues such as whether or not to premedicate and the choice of premedication(s) must be individualized. In clinical studies, patients scheduled to be anesthetized with SUPRANE frequently received IV preanesthetic medication, such as opioid and/or benzodiazepine.

Induction

In adults, some premedicated with opioid, a frequent starting concentration was 3% SUPRANE, increased in 0.5-1.0% increments every 2 to 3 breaths. End-tidal concentrations of 4-11%, SUPRANE with and without N₂O, produced anesthesia within 2 to 4 minutes. When SUPRANE was tested as the primary anesthetic induction agent, the incidence of upper airway irritation (apnea, breathholding, laryngospasm, coughing and secretions) was high. During induction in adults, the overall incidence of oxyhemoglobin desaturation (SpO₂ < 90%) was 6%.

After induction in adults with an intravenous drug such as thiopental or propofol, SUPRANE can be started at approximately 0.5-1 MAC, whether the carrier gas is O₂ or N₂O/O₂.

Inspired concentrations of SUPRANE greater than 12% have been safely administered to patients, particularly during induction of anesthesia. Such concentrations will proportionately dilute the concentration of oxygen; therefore, maintenance of an adequate concentration of oxygen may require a reduction of nitrous oxide or air if these gases are used concurrently.

Maintenance

Surgical levels of anesthesia in adults may be maintained with concentrations of 2.5-8.5% SUPRANE with or without the concomitant use of nitrous oxide. In children, surgical levels of anesthesia may be maintained with concentrations of 5.2-10% SUPRANE with or without the concomitant use of nitrous oxide.

During the maintenance of anesthesia with inflow rates of 2 L/min or more, the alveolar concentration of SUPRANE will usually be within 10% of the inspired concentration [F_A/F_I , see Figure 2 in CLINICAL PHARMACOLOGY].

During the maintenance of anesthesia, increasing concentrations of SUPRANE produce dose-dependent decreases in blood pressure. Excessive decreases in blood pressure may be due to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of SUPRANE.

Concentrations of SUPRANE exceeding 1 MAC may increase heart rate. Thus with this drug, an increased heart rate may not serve reliably as a sign of inadequate anesthesia.

Maintenance Of Anesthesia In Intubated Pediatric Patients

SUPRANE is indicated for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation.

SUPRANE, with or without N₂O, and halothane, with or without N₂O were studied in three clinical trials of pediatric patients aged 2 weeks to 12 years (median 2 years) and ASA physical status I or II. The concentration of SUPRANE required for maintenance of general anesthesia is age-dependent.

Changes in blood pressure during maintenance of and recovery from anesthesia with SUPRANE /N₂O/O₂ are similar to those observed with halothane/N₂O/O₂. Heart rate during maintenance of anesthesia is approximately 10 beats per minute faster with SUPRANE than with halothane. Patients were judged fit for discharge from post-anesthesia care units within one hour with both SUPRANE and halothane. There were no differences in the incidence of nausea and vomiting between patients receiving SUPRANE or halothane.

Recovery

The recovery from general anesthesia should be assessed carefully before patients are discharged from the post anesthesia care unit (PACU).

Use In Patients With Coronary Artery Disease

In patients with coronary artery disease, maintenance of normal hemodynamics is important to prevent myocardial ischemia. A rapid increase in desflurane concentration is associated with marked increase in pulse rate, mean arterial pressure and levels of epinephrine and norepinephrine. SUPRANE should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or patients where increases in heart rate or blood pressure are undesirable. It should be used with other medications, preferably intravenous opioids and hypnotics.

Neurosurgical Use

SUPRANE may produce a dose-dependent increase in cerebrospinal fluid pressure (CSFP) when administered to patients with intracranial space occupying lesions. SUPRANE should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) until cerebral decompression in patients with known or suspected increases in CSFP. Appropriate attention must be paid to maintain cerebral perfusion pressure.

The use of SUPRANE is contraindicated in the following conditions:

• Known or suspected genetic susceptibility to malignant hyperthermia.
• Patients in whom general anesthesia is contraindicated.
• Induction of anesthesia in pediatric patients.
• Patients with known sensitivity to SUPRANE or to other halogenated agents.
• Patients with a history of moderate to severe hepatic dysfunction following anesthesia with SUPRANE or other halogenated agents and not otherwise explained.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Malignant Hyperthermia

In susceptible individuals, potent inhalation anesthetic agents may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. In genetically susceptible pigs, desflurane induced malignant hyperthermia. The clinical syndrome is signaled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia: acute hypoxia, hypercapnia, and hypovolemia.

Treatment of malignant hyperthermia includes discontinuation of triggering agents, administration of intravenous dantrolene sodium, and application of supportive therapy. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be monitored and sustained if possible.

Fatal outcome of malignant hyperthermia has been reported with desflurane.

Perioperative Hyperkalemia

Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.

Respiratory Adverse Reactions In Pediatric Patients

SUPRANE is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm and secretions.

Children, particularly if 6 years old or younger, who are under an anesthetic maintenance of SUPRANE delivered via laryngeal mask airway (LMA™ mask) are at increased risk for adverse respiratory reactions, e.g., coughing and laryngospasm, especially with removal of the laryngeal mask airway under deep anesthesia. Therefore, closely monitor these patients for signs and symptoms associated with laryngospasm and treat accordingly.

When SUPRANE is used for maintenance of anesthesia in children with asthma or a history of recent upper airway infection, there is an increased risk for airway narrowing and increases in airway resistance. Therefore, closely monitor these patients for signs and symptoms associated with airway narrowing and treat accordingly.

Interactions With Desiccated Carbon Dioxide Absorbents

Desflurane like some other inhalation anesthetics, can react with desiccated carbon dioxide (CO₂) absorbents to produce carbon monoxide that may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO₂ canister at high flow rates over many hours or days. When a clinician suspects that CO₂ absorbent may be desiccated, it should be replaced before the administration of SUPRANE.

Hepatobiliary Disorders

With the use of halogenated anesthetics, disruption of hepatic function, icterus and fatal liver necrosis have been reported; such reactions appear to indicate hypersensitivity. As with other halogenated anesthetic agents, SUPRANE may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics. Cirrhosis, viral hepatitis or other pre-existing hepatic disease may be a reason to select an anesthetic other than a halogenated anesthetic. As with all halogenated anesthetics, repeated anesthesia within a short period of time should be approached with caution.

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..

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 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.

Laboratory Findings

Transient elevations in glucose and white blood cell count may occur as with use of other anesthetic agents.

Postoperative Agitation In Children

Emergence from anesthesia in children may evoke a brief state of agitation that may hinder cooperation.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of desflurane have not been conducted.

Mutagenesis

In vitro and in vivo genotoxicity studies did not demonstrate mutagenicity or chromosomal damage by desflurane. Tests for genotoxicity included the Ames mutation assay, the metaphase analysis of human lymphocytes, and the mouse micronucleus assay.

Impairment Of Fertility

In a study in which male animals were administered 8.2% desflurane (60% oxygen) for either 0.5, 1.0, or 4.0 hours per day beginning 63 days prior to mating and female animals were administered the same doses of desflurane for 14 days prior to mating through Lactation Day 21, there were no adverse effects on fertility in the 1.0 hour per day treatment group. However, reduced male and female fertility was noted in the 4 hour a day group. A dose dependent increase in mortality and decreased body weight gain was note in all treatment groups.

Use In Specific Populations

Pregnancy

Risk Summary

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, embryo-fetal toxicity (reduced viable fetuses and/or increased post-implantation loss) was noted in pregnant rats and rabbits administered 1 MAC desflurane for 4 hours a day (4 MAC-hours/day) during organogenesis.

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans [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 2-4% and 1520%, respectively.

Clinical Considerations

Labor or Delivery

The safety of SUPRANE during labor or delivery has not been demonstrated. SUPRANE is a uterine-relaxant.

Data

Animal Data

Pregnant rats were exposed to 8.2% desflurane (1 MAC; 60% oxygen) for 0.5, 1.0, or 4.0 hours (0.5, 1.0, or 4.0 MAC-hours) per day during organogenesis (Gestation Day 6-15).

Embryo-fetal toxicity (increased post-implantation loss and reduced viable fetuses) was noted in the 4 hour treatment group in the presence of maternal toxicity (reduced body weight gain). There was no evidence of malformations in any group.

Pregnant rabbits were exposed to 8.9% desflurane (1 MAC; 60% oxygen) for 0.5, 1.0, or 3.0 hours per day during organogenesis (Gestation Days 6-18). Fetal toxicity (reduced viable fetuses) was noted in the 3 hour treatment group in the presence of maternal toxicity (reduced body weight). There was no evidence of malformations in any group.

Pregnant rats were exposed to 8.2% desflurane (1 MAC; 60% oxygen) for 0.5, 1.0, or 4.0 hours per day from late gestation and through lactation (Gestation Day 15 to Lactation Day 21). Pup body weights were reduced in the 4 hours per day group in the presence of maternal toxicity (increased mortality and reduced body weight gain). This study did not evaluate neurobehavioral function including learning and memory or reproductive behavior in the first generation (F1) pups.

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.

Lactation

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

Pediatric Use

Respiratory Adverse Reactions In Pediatric Patients

SUPRANE is indicated for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation.

Is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing (26%), laryngospasm (13%) and secretions (12%).

Children, particularly if 6 years old or younger, who are under an anesthetic maintenance of SUPRANE delivered via laryngeal mask airway (LMA™ mask) are at increased risk for adverse respiratory reactions, e.g., coughing and laryngospasm, especially with removal of the laryngeal mask airway under deep anesthesia. Therefore, closely monitor these patients for signs and symptoms associated with laryngospasm and treat accordingly.

When SUPRANE is used for maintenance of anesthesia in children with asthma or a history of recent upper airway infection, there is an increased risk for airway narrowing and increases in airway resistance. Therefore, closely monitor these patients for signs and symptoms associated with airway narrowing and treat accordingly.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as SUPRANE, 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.

Geriatric Use

The minimum alveolar concentration (MAC) of SUPRANE decreases with increasing patient age. The dose should be adjusted accordingly. The average MAC for SUPRANE in a 70 year old patient is two-thirds the MAC for a 20 year old patient.

Renal Impairment

Concentrations of 1-4% SUPRANE in nitrous oxide/oxygen have been used in patients with chronic renal or hepatic impairment and during renal transplantation surgery.

Because of minimal metabolism, a need for dose adjustment in patients with renal and hepatic impairment is not to be expected.

Nine patients receiving desflurane (N=9) were compared to 9 patients receiving isoflurane, all with chronic renal insufficiency (serum creatinine 1.5-6.9 mg/dL). No differences in hematological or biochemical tests, including renal function evaluation, were seen between the two groups. Similarly, no differences were found in a comparison of patients receiving either desflurane (N=28) or isoflurane (N=30) undergoing renal transplant.

Hepatic Impairment

Eight patients receiving SUPRANE were compared to six patients receiving isoflurane, all with chronic hepatic disease (viral hepatitis, alcoholic hepatitis, or cirrhosis). No differences in hematological or biochemical tests, including hepatic enzymes and hepatic function evaluation, were seen.

SIDE EFFECTS

The following serious adverse reactions with the use of STAXYN (vardenafil) are discussed elsewhere in the labeling:

• Cardiovascular effects
• Priapism
• QT Prolongation
• Effects on eye
• Sudden hearing loss

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

STAXYN

Safety of STAXYN was evaluated in two identical multi-national, randomized, double-blind, placebo-controlled trials. In both pivotal studies, enrollment was stratified so that approximately 50% of patients were ≥ 65 years old. Approximately 8% (n=29) were ≥ 75 years old. An integrated analysis of both studies included a total of 355 subjects that received STAXYN compared to 340 subjects that received placebo (mean age was 61.7, range 21.0 to 88.0; 68% White, 5% Black, 6% Asian, 11% Hispanic and 11% Other). The discontinuation rates due to adverse reactions were 1.4% for STAXYN compared to 0.6% for placebo. Table 1 below details the most frequently reported adverse reactions.

Table 1: Adverse drug reactions reported by ≥ 2% of the patients treated with STAXYN and more frequent on drug than placebo in controlled trials

Adverse drug reactions reported in the STAXYN placebo controlled trials were comparable to the adverse drug reactions reported in earlier vardenafil film-coated tablets placebo controlled trials.

All Vardenafil Studies

Vardenafil film-coated tablets and STAXYN has been administered to over 17,000 men (mean age 54.5, range 18 - 89 years; 70% White, 5% Black, 13% Asian, 4% Hispanic and 8% Other) during controlled and uncontrolled clinical trials worldwide. The number of patients treated for 6 months or longer was 3357, and 1350 patients were treated for at least 1 year.

In the placebo-controlled clinical trials for vardenafil film-coated tablets and STAXYN, the discontinuation rate due to adverse events was 1.9% for vardenafil compared to 0.8% for placebo. Placebo-controlled trials suggested a dose effect in the incidence of some adverse reactions (for example, dizziness, headache, flushing, dyspepsia, nausea, nasal congestion) over the 5 mg, 10 mg, and 20 mg doses of vardenafil film-coated tablets.

The following section identifies additional, less frequent adverse reactions (<2%) reported during the clinical development of vardenafil film-coated tablets and STAXYN. Excluded from this list are those adverse reactions that are infrequent and minor, those events that may be commonly observed in the absence of drug therapy, and those events that are not reasonably associated with the drug:

Body as a whole: allergic edema and angioedema, feeling unwell, allergic reactions, chest pain Auditory: tinnitus, vertigo

Cardiovascular: palpitation, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension

Digestive: nausea, gastrointestinal and abdominal pain, dry mouth, diarrhea, gastroesophageal reflux disease, gastritis, vomiting, increase in transaminases

Musculoskeletal: increase in creatine phosphokinase (CPK), increased muscle tone and cramping, myalgia

Nervous: paresthesia and dysesthesia, somnolence, sleep disorder, syncope, amnesia, seizure

Respiratory: dyspnea, sinus congestion

Skin and appendages: erythema, rash

Ophthalmologic: visual disturbance, ocular hyperemia, visual color distortions, eye pain and eye discomfort, photophobia, increase in intraocular pressure, conjunctivitis

Urogenital: increase in erection, priapism

Postmarketing Experience

The following adverse reactions have been identified during post approval use of vardenafil in the film-coated tablet formulation. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.

Ophthalmologic

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.

Visual disturbances including vision loss (temporary or permanent), such as visual field defect, retinal vein occlusion, and reduced visual acuity, have also been reported rarely in postmarketing experience. It is not possible to determine whether these events are related directly to the use of vardenafil.

Neurologic

Seizure, seizure recurrence and transient global amnesia have been reported postmarketing in temporal association with vardenafil.

Otologic

Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. In some cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of vardenafil, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors.

DRUG INTERACTIONS

The drug interaction studies described below were conducted using vardenafil film-coated tablets.

Potential For Pharmacodynamic Interactions With STAXYN

Nitrates

Concomitant use of STAXYN and nitrates is contraindicated. The blood pressure lowering effects of sublingual nitrates (0.4 mg) taken 1 and 4 hours after vardenafil and increases in heart rate when taken at 1, 4 and 8 hours after vardenafil were potentiated by a 20 mg dose of vardenafil in healthy middle-aged subjects. These effects were not observed when vardenafil 20 mg was taken 24 hours before the nitroglycerin (NTG). Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of STAXYN and nitrates is contraindicated.

Alpha-Blockers

Patients taking alpha-blockers should not initiate vardenafil therapy with STAXYN. Patients treated with alpha-blockers who have previously used vardenafil film-coated tablets may be switched to STAXYN at the advice of their healthcare provider. Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including STAXYN and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with co-administration of vardenafil with alfuzosin, terazosin or tamsulosin.

Antihypertensives

STAXYN may add to the blood pressure lowering effect of antihypertensive agents. In a clinical pharmacology study of patients with erectile dysfunction, single doses of 20 mg vardenafil caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1.

Alcohol

Vardenafil 20 mg did not potentiate the hypotensive effects of alcohol during the 4-hour observation period in healthy volunteers when administered with alcohol (0.5 g/kg body weight: approximately 40 mL of absolute alcohol in a 70 kg person). Alcohol and vardenafil plasma levels were not altered when dosed simultaneously.

Effect Of Other Drugs On Vardenafil

In vitro studies

Studies in human liver microsomes showed that vardenafil is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP2C9. Therefore, inhibitors of these enzymes are expected to reduce vardenafil clearance.

In vivo studies

Do not use STAXYN with moderate and potent CYP3A4 inhibitors such as erythromycin, grapefruit juice, clarithromycin, ketoconazole, itraconazole, indinavir, saquinavir, atazanavir, ritonavir as the systemic concentration of vardenafil is increased in their presence.

Potent CYP3A4 inhibitors

Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil area under the curve (AUC) and a 4-fold increase in maximum concentration (Cmax) when co-administered with vardenafil 5 mg in healthy volunteers.

Indinavir (800 mg t.i.d.) co-administered with vardenafil 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil Cmax and a 2-fold increase in vardenafil half-life.

Ritonavir (600 mg b.i.d.) co-administered with vardenafil 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13fold increase in vardenafil Cmax. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9.

Moderate CYP3A4 inhibitors

Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in vardenafil Cmax when co-administered with vardenafil 5 mg in healthy volunteers.

Other Drug Interactions

No pharmacokinetic interactions were observed between vardenafil and the following drugs: glyburide, warfarin, digoxin, an antacid based on magnesium-aluminum hydroxide, and ranitidine. In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters.

Cimetidine (400 mg b.i.d.) had no effect on AUC and Cmax of vardenafil when co-administered with 20 mg vardenafil in healthy volunteers.

Effects Of Vardenafil On Other Drugs

In Vitro Studies

Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >100 micromolar). Weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4) were found, but Ki values were in excess of plasma concentrations achieved following dosing. The most potent inhibitory activity was observed for vardenafil metabolite M1, which had a Ki of 1.4 micromolar toward CYP3A4, which is about 20 times higher than the M1 Cmax values after an 80 mg vardenafil dose.

In Vivo Studies

Nifedipine

Vardenafil 20 mg (film-coated tablets), when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the relative AUC or Cmax of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of vardenafil when taken in combination. STAXYN, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily in patients whose hypertension was controlled with nifedipine, produced mean additional supine systolic/diastolic blood pressure reductions of 3/4 mmHg (age group 65 to 69 years) and 5/5 mmHg (age group 70 to 80 years) compared to placebo.

Ritonavir And Indinavir

Upon concomitant administration of 5 mg vardenafil with 600 mg b.i.d. ritonavir, the Cmax and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of vardenafil (film-coated tablets) with 800 mg t.i.d. indinavir, the Cmax and AUC of indinavir were reduced by 40% and 30%, respectively.

Aspirin

Vardenafil 10 mg and 20 mg did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).

Other Interactions

Vardenafil had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).

Risk Summary

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, embryo-fetal toxicity (reduced viable fetuses and/or increased post-implantation loss) was noted in pregnant rats and rabbits administered 1 MAC desflurane for 4 hours a day (4 MAC-hours/day) during organogenesis.

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans [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 2-4% and 1520%, respectively.

Clinical Considerations

Labor or Delivery

The safety of SUPRANE during labor or delivery has not been demonstrated. SUPRANE is a uterine-relaxant.

Data

Animal Data

Pregnant rats were exposed to 8.2% desflurane (1 MAC; 60% oxygen) for 0.5, 1.0, or 4.0 hours (0.5, 1.0, or 4.0 MAC-hours) per day during organogenesis (Gestation Day 6-15).

Embryo-fetal toxicity (increased post-implantation loss and reduced viable fetuses) was noted in the 4 hour treatment group in the presence of maternal toxicity (reduced body weight gain). There was no evidence of malformations in any group.

Pregnant rabbits were exposed to 8.9% desflurane (1 MAC; 60% oxygen) for 0.5, 1.0, or 3.0 hours per day during organogenesis (Gestation Days 6-18). Fetal toxicity (reduced viable fetuses) was noted in the 3 hour treatment group in the presence of maternal toxicity (reduced body weight). There was no evidence of malformations in any group.

Pregnant rats were exposed to 8.2% desflurane (1 MAC; 60% oxygen) for 0.5, 1.0, or 4.0 hours per day from late gestation and through lactation (Gestation Day 15 to Lactation Day 21). Pup body weights were reduced in the 4 hours per day group in the presence of maternal toxicity (increased mortality and reduced body weight gain). This study did not evaluate neurobehavioral function including learning and memory or reproductive behavior in the first generation (F1) pups.

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.

The following serious adverse reactions with the use of STAXYN (vardenafil) are discussed elsewhere in the labeling:

• Cardiovascular effects
• Priapism
• QT Prolongation
• Effects on eye
• Sudden hearing loss

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

STAXYN

Safety of STAXYN was evaluated in two identical multi-national, randomized, double-blind, placebo-controlled trials. In both pivotal studies, enrollment was stratified so that approximately 50% of patients were ≥ 65 years old. Approximately 8% (n=29) were ≥ 75 years old. An integrated analysis of both studies included a total of 355 subjects that received STAXYN compared to 340 subjects that received placebo (mean age was 61.7, range 21.0 to 88.0; 68% White, 5% Black, 6% Asian, 11% Hispanic and 11% Other). The discontinuation rates due to adverse reactions were 1.4% for STAXYN compared to 0.6% for placebo. Table 1 below details the most frequently reported adverse reactions.

Table 1: Adverse drug reactions reported by ≥ 2% of the patients treated with STAXYN and more frequent on drug than placebo in controlled trials

Adverse drug reactions reported in the STAXYN placebo controlled trials were comparable to the adverse drug reactions reported in earlier vardenafil film-coated tablets placebo controlled trials.

All Vardenafil Studies

Vardenafil film-coated tablets and STAXYN has been administered to over 17,000 men (mean age 54.5, range 18 - 89 years; 70% White, 5% Black, 13% Asian, 4% Hispanic and 8% Other) during controlled and uncontrolled clinical trials worldwide. The number of patients treated for 6 months or longer was 3357, and 1350 patients were treated for at least 1 year.

In the placebo-controlled clinical trials for vardenafil film-coated tablets and STAXYN, the discontinuation rate due to adverse events was 1.9% for vardenafil compared to 0.8% for placebo. Placebo-controlled trials suggested a dose effect in the incidence of some adverse reactions (for example, dizziness, headache, flushing, dyspepsia, nausea, nasal congestion) over the 5 mg, 10 mg, and 20 mg doses of vardenafil film-coated tablets.

The following section identifies additional, less frequent adverse reactions (<2%) reported during the clinical development of vardenafil film-coated tablets and STAXYN. Excluded from this list are those adverse reactions that are infrequent and minor, those events that may be commonly observed in the absence of drug therapy, and those events that are not reasonably associated with the drug:

Body as a whole: allergic edema and angioedema, feeling unwell, allergic reactions, chest pain Auditory: tinnitus, vertigo

Cardiovascular: palpitation, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension

Digestive: nausea, gastrointestinal and abdominal pain, dry mouth, diarrhea, gastroesophageal reflux disease, gastritis, vomiting, increase in transaminases

Musculoskeletal: increase in creatine phosphokinase (CPK), increased muscle tone and cramping, myalgia

Nervous: paresthesia and dysesthesia, somnolence, sleep disorder, syncope, amnesia, seizure

Respiratory: dyspnea, sinus congestion

Skin and appendages: erythema, rash

Ophthalmologic: visual disturbance, ocular hyperemia, visual color distortions, eye pain and eye discomfort, photophobia, increase in intraocular pressure, conjunctivitis

Urogenital: increase in erection, priapism

Postmarketing Experience

The following adverse reactions have been identified during post approval use of vardenafil in the film-coated tablet formulation. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.

Ophthalmologic

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.

Visual disturbances including vision loss (temporary or permanent), such as visual field defect, retinal vein occlusion, and reduced visual acuity, have also been reported rarely in postmarketing experience. It is not possible to determine whether these events are related directly to the use of vardenafil.

Neurologic

Seizure, seizure recurrence and transient global amnesia have been reported postmarketing in temporal association with vardenafil.

Otologic

Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. In some cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of vardenafil, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors.

The symptoms of overdosage of SUPRANE can present as a deepening of anesthesia, cardiac and/or respiratory depression in spontaneously breathing patients, and cardiac depression in ventilated patients in whom hypercapnia and hypoxia may occur only at a late stage. In the event of overdosage, or suspected overdosage, take the following actions: discontinue administration of SUPRANE, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function.

Changes in the clinical effects of SUPRANE rapidly follow changes in the inspired concentration. The duration of anesthesia and selected recovery measures for SUPRANE are given in the following tables:

In 178 female outpatients undergoing laparoscopy, premedicated with fentanyl (1.5-2.0 μg/kg), anesthesia was initiated with propofol 2.5 mg/kg, desflurane/N₂O 60% in O₂ or desflurane/O₂ alone. Anesthesia was maintained with either propofol 1.5-9.0 mg/kg/hr, desflurane 2.6-8.4% in N₂O 60% in O₂, or desflurane 3.1-8.9% in O₂.

Emergence and Recovery After Outpatient Laparoscopy 178 Females, Ages 20-47 Times in Minutes: Mean ± SD (Range)

In 88 unpremedicated outpatients, anesthesia was initiated with thiopental 3-9 mg/kg or desflurane in O₂. Anesthesia was maintained with isoflurane 0.7-1.4% in N₂O 60%, desflurane 1.8-7.7% in N₂O 60%, or desflurane 4.4-11.9% in O₂.

Emergence and Recovery Times in Outpatient Surgery 46 Males, 42 Females, Ages 19-70 Times in Minutes: Mean ± SD (Range)

Recovery from anesthesia was assessed at 30, 60, and 90 minutes following 0.5 MAC desflurane (3%) or isoflurane (0.6%) in N₂O 60% using subjective and objective tests. At 30 minutes after anesthesia, only 43% of patients in the isoflurane group were able to perform the psychometric tests compared to 76% in the SUPRANE group (p < 0.05).

Recovery Tests: Percent of Preoperative Baseline Values 16 Males, 22 Females, Ages 20-65 Percent: Mean ± SD

SUPRANE was studied in twelve volunteers receiving no other drugs. Hemodynamic effects during controlled ventilation (PaCO₂ 38 mm Hg) were:

Hemodynamic Effects of Desflurane During Controlled Ventilation 12 Male Volunteers, Ages 16-26 Mean ± SD (Range)

When the same volunteers breathed spontaneously during desflurane anesthesia, systemic vascular resistance and mean arterial blood pressure decreased; cardiac index, heart rate, stroke volume, and central venous pressure (CVP) increased compared to values when the volunteers were conscious. Cardiac index, stroke volume, and CVP were greater during spontaneous ventilation than during controlled ventilation.

During spontaneous ventilation in the same volunteers, increasing the concentration of SUPRANE from 3% to 12% decreased tidal volume and increased arterial carbon dioxide tension and respiratory rate. The combination of N₂O 60% with a given concentration of desflurane gave results similar to those with desflurane alone. Respiratory depression produced by desflurane is similar to that produced by other potent inhalation agents.

The use of desflurane concentrations higher than 1.5 MAC may produce apnea.

Figure 1:PaCO₂ During Spontaneous Ventilation in Unstimulated Volunteers

Due to the volatile nature of desflurane in plasma samples, the washin-washout profile of desflurane was used as a surrogate of plasma pharmacokinetics. SUPRANE is a volatile liquid inhalation anesthetic minimally biotransformed in the liver in humans. Less than 0.02% of the desflurane absorbed can be recovered as urinary metabolites (compared to 0.2% for isoflurane). Eight healthy male volunteers first breathed 70% N₂O/30% O₂ for 30 minutes and then a mixture of desflurane 2.0%, isoflurane 0.4%, and halothane 0.2% for another 30 minutes. During this time, inspired and end-tidal concentrations (FI and FA) were measured. The FA/FI (washin) value at 30 minutes for desflurane was 0.91, compared to 1.00 for N₂O, 0.74 for isoflurane, and 0.58 for halothane (see Figure 2). The washin rates for halothane and isoflurane were similar to literature values. The washin was faster for desflurane than for isoflurane and halothane at all time points. The FA/FAO (washout) value at 5 minutes was 0.12 for desflurane, 0.22 for isoflurane, and 0.25 for halothane (see Figure 3). The washout for desflurane was more rapid than that for isoflurane and halothane at all elimination time points. By 5 days, the FA/FAO for desflurane is 1/20th of that for halothane or isoflurane.

Figure 2: Desflurane Washin

Figure 3: Desflurane Washout