The number of patients treated for 6 months or longer was , and 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.
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. 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: 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: 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. The blood pressure lowering effects of sublingual nitrates 0.
These effects were not observed when vardenafil 20 mg was taken 24 hours before the nitroglycerin NTG. 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.
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.
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. Alcohol and vardenafil plasma levels were not altered when dosed simultaneously. Potent CYP3A4 inhibitors Ketoconazole mg once daily produced a 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.
Other Drug Interactions No pharmacokinetic interactions were observed between vardenafil and the following drugs: In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters. Cimetidine mg b. The most potent inhibitory activity was observed for vardenafil metabolite M1, which had a Ki of 1. 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. Ritonavir And Indinavir Upon concomitant administration of 5 mg vardenafil with mg b. Upon administration of 10 mg of vardenafil film-coated tablets with mg t. 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.
In genetically susceptible pigs, desflurane induced malignant hyperthermia. Some of these nonspecific signs may also appear during light anesthesia: 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 [see Clinical Studies ]. 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. 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.
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. 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. 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. 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.
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. Data Animal Data Pregnant rats were exposed to 8. 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. Fetal toxicity reduced viable fetuses was noted in the 3 hour treatment group in the presence of maternal toxicity reduced body weight.
Pregnant rats were exposed to 8. 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 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 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. Lactation It is not known whether this drug is excreted in human milk. 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 dose should be adjusted accordingly.
Because of minimal metabolism , a need for dose adjustment in patients with renal and hepatic impairment is not to be expected. No differences in hematological or biochemical tests, including renal function evaluation, were seen between the two groups. 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.
In the event of overdosage, or suspected overdosage, take the following actions: Known or suspected genetic susceptibility to malignant hyperthermia. Patients in whom general anesthesia is contraindicated. Induction of anesthesia in pediatric patients. In female outpatients undergoing laparoscopy , premedicated with fentanyl 1.