Flumazenil Injection SDZ Product Monograph

INDICATIONS AND CLINICAL USE

Flumazenil Injection SDZ is indicated for the complete or partial reversal of the central sedative effects of benzodiazepines. It may therefore be used in anesthesia and intensive care in the following situations:

• Termination of general anesthesia induced and/or maintained with benzodiazepines.
• Reversal of benzodiazepine sedation in short diagnostic and therapeutic procedures.
• For the diagnosis and/or as an adjunct to supportive measures used for the management of deliberate or accidental benzodiazepine overdosage.

Geriatrics (> 65 years of age):

Elderly patients may be more sensitive to the effects of flumazenil. For a brief description, see PRECAUTIONS-Use in the Elderly

Pediatrics (< 18 years of age):

The safety and effectiveness of flumazenil in children below the age of 18 has not been established.

CONTRAINDICATIONS

Flumazenil Injection SDZ is contraindicated:

• In patients with known hypersensitivity to flumazenil or to benzodiazepines.
• In epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. The abrupt suppression of the protective effect of benzodiazepines may induce convulsions in epileptic patients.
• In patients who are showing signs of serious cyclic antidepressant overdose (see PRECAUTIONS).
• In patients who have been given a benzodiazepine for a potentially life-threatening condition (e.g. intracranial pressure).

WARNINGS

IN VIEW OF THE SHORT DURATION OF ACTION OF FLUMAZENIL INJECTION SDZ AND THE POSSIBLE NEED FOR REPEAT DOSES, THE PATIENT SHOULD REMAIN CLOSELY MONITORED UNTIL ALL POSSIBLE CENTRAL BENZODIAZEPINE EFFECTS HAVE SUBSIDED.

THE IMMEDIATE AVAILABILITY OF OXYGEN, RESUSCITATIVE EQUIPMENT AND SKILLED PERSONNEL FOR THE MAINTENANCE OF AIRWAY, VENTILATION AND CARDIAC FUNCTION SHOULD BE ENSURED BEFORE THE ADMINISTRATION OF ANY BENZODIAZEPINE OR FLUMAZENIL INJECTION SDZ.

Resedation: Flumazenil is a competitive inhibitor of benzodiazepines at the receptor site and does not affect the pharmacokinetics of benzodiazepines. Thus, when the effect of flumazenil wears off, the patient returns to the point of residual sedation that would have been present at that time had flumazenil not been given. In patients administered large doses of long-acting benzodiazepines or in critically ill patients, this could be deep sedation. In a US clinical study in patients with benzodiazepine intoxication, 90/133 (67.7%) patients became resedated. Therefore, Flumazenil Injection SDZ should be administered only when the continued observation of patients for recurrence of sedation, respiratory depression, or residual benzodiazepine effects can be assured.

Respiration: When used in anesthesiology at the end of surgery, Flumazenil Injection SDZ should not be given until the effects of neuromuscular blockade have been completely antagonized and careful monitoring of the respiratory depressant effect of opiate analgesics has been assured. After the benzodiazepine has been antagonized with Flumazenil Injection SDZ, any residual respiratory depressant effect of benzodiazepines and other agents, such as opiates, may require interventions such as establishing an airway and assisted ventilation.

The ability of flumazenil to reverse benzodiazepine-induced respiratory depression is equivocal; in some studies residual effects of benzodiazepines on respiration were still present despite reversal of sedation.

Seizures: Rapid intravenous injections should be avoided in patients treated for long periods of time and/or with high doses of benzodiazepines, as Flumazenil Injection SDZ may trigger withdrawal symptoms (e.g. convulsions, agitation, anxiety, emotional lability as well as mild confusion and sensory distortions). Seizures have been reported in patients known to suffer from epilepsy, or severe hepatic impairment, particularly after long-term treatment with benzodiazepines or in cases of mixed-drug overdose. Most convulsions associated with flumazenil administration require treatment and have been successfully managed with benzodiazepines, phenytoin or barbiturates.

PRECAUTIONS

General: In high-risk patients (e.g., patients treated with benzodiazepines for long periods of time, overdose with signs of cyclic antidepressant overdosage), the advantages of counteracting benzodiazepine-related sedation should be weighed against the drawbacks of rapid awakening.

Postoperative pain must be taken into account. Following a major intervention, it may be preferable to maintain a moderate degree of sedation.

Flumazenil Injection SDZ is not recommended either as a treatment for benzodiazepine dependence or for the management of protracted benzodiazepine abstinence syndromes.

Anxiety and Panic Disorder: The dosage of Flumazenil Injection SDZ should be adjusted carefully in patients suffering from preoperative anxiety or having a history of chronic or episodic anxiety. In anxious patients, particularly those with coronary heart disease, it is preferable to maintain a degree of sedation throughout the early postoperative period rather than bring about complete arousal.

Flumazenil has been reported to provoke panic attacks in patients with history of panic disorders.

Instructions to Patients Upon Discharge: Patients who have received Flumazenil Injection SDZ to reverse the effects of benzodiazepine sedation should be instructed, if possible in writing, not to drive, to operate machinery or to engage in any other physically or mentally demanding activity for 24 hours or until the effects of the benzodiazepine have subsided, since the effect of the benzodiazepine may return. Patients should also be warned not to take alcohol, or drugs not prescribed by their physician, until the effects of the benzodiazepines have subsided.

Use in Children: The safety and effectiveness of flumazenil in children below the age of 18 has not been established.

Use in the Elderly: In the absence of data on the use of flumazenil in elderly patients, it should be borne in mind that this population is generally more sensitive to the effects of drugs and should be treated with due caution.

Use in Pregnancy and Lactation: Although studies in animals have not shown evidence of embryotoxicity or teratogenicity (see REPRODUCTION AND TERATOLOGY), Flumazenil Injection SDZ should be used during pregnancy only, if in the opinion of the treating physician, the possible benefit to the patient outweighs the potential risks to the fetus.

It is not known whether flumazenil is excreted in human milk. For this reason, breast-feeding should be interrupted for 24 hours when Flumazenil Injection SDZ is used during lactation.

Use in Hepatic Impairment: In patients with liver insufficiency, the elimination of flumazenil can be delayed. Caution should be exercised with initial and/or repeated dosing to patients with liver disease. (see ACTION AND CLINICAL PHARMACOLOGY-Hepatic Impairment, DOSAGE AND ADMINISTRATION).

Seizures have been reported in patients known to suffer from severe hepatic impairment, particularly after long-term treatment with benzodiazepines or in cases of mixed-drug overdose.

Use in Renal Impairment

No dosage adjustments are necessary in patients with renal impairment.

Use in Respiratory Disease

The primary treatment of patients with serious lung disease who experience serious respiratory depression due to benzodiazepines should be given appropriate ventilatory support, rather than administration of flumazenil.

Use in Acute Myocardial Infarction or Cardiac Arrhythmias: Flumazenil abruptly terminates the effects of benzodiazepines. As a result, sympathetic tone may be increased and thus, cardiac electrical instability enhanced. Consequently, caution is advised when administering Flumazenil Injection SDZ to patients with myocardial infarction or cardiac arrhythmias.

Use in Patients with Increased Intracranial Pressure Receiving Benzodiazepines (e.g. head injury, brain tumour, intracranial hemorrhage): In patients with increased intracranial pressure, flumazenil may further increase intracranial pressure, cerebral perfusion pressure, or precipitate convulsions. In such patients, flumazenil should be used with extreme caution and only by practitioners prepared to manage such complications, should they occur.

Multiple Drug Overdosage: Particular caution is necessary when using Flumazenil Injection SDZ in cases of multiple drug overdosage, since the toxic effects (cardiac arrhythmias and/or convulsions) of other psychotropic drugs, especially cyclic antidepressants, may increase as the effects of benzodiazepines subside.

Patients should be evaluated for the signs and symptoms (autonomic, neurological or cardiovascular) of a cyclic antidepressant overdose. A diagnostic ECG can be used to confirm the presence of these agents; a QRS duration of 0.1 seconds or greater indicates a serious overdosage with cyclic antidepressants, which should be treated with appropriate measures. Depending on the extent of involvement of benzodiazepines in the multiple drug overdose, this may or may not include Flumazenil Injection SDZ.

Use in the ICU: Flumazenil Injection SDZ should be used with caution in the Intensive Care Unit because of the increased risk of unrecognized benzodiazepine dependence in such settings. Flumazenil may produce convulsions in patients physically dependent on benzodiazepine (see WARNINGS-Seizures).

DRUG INTERACTIONS

Interactions with central nervous system depressants other than benzodiazepines have not been studied specifically.

Flumazenil blocks the central effects of benzodiazepines by competitive interaction at the receptor level; the effects of non-benzodiazepines which act via the benzodiazepine receptor, such as zopiclone, triazolopyridazines and others, are also blocked. However, flumazenil does not reverse the effects of drugs that do not act via this route, such as opioids.

The pharmacokinetics of flumazenil are unaltered in the presence of benzodiazepines, and similarly, flumazenil does not affect the kinetics of benzodiazepines.

There is no pharmacokinetic interaction between ethanol and flumazenil.

ADVERSE REACTIONS

Flumazenil is generally well tolerated. In postoperative use, nausea and/or vomiting are observed, particularly if opiates have also been employed. Flushing has also been noted. If patients are awakened too rapidly, they may become agitated, anxious or fearful. Transient increases in blood pressure and heart rate may also occur.

Excessively and/or rapidly injected doses of flumazenil may induce benzodiazepine withdrawal symptoms such as anxiety attacks, tachycardia, dizziness and sweating in patients on long-term benzodiazepine treatment.

Although clinical experience with flumazenil is limited, seizures and/or cardiac arrhythmias have been observed in patients who are physically dependent on benzodiazepines, and in multiple drug overdose, particularly in the presence of tricyclic antidepressants.

Flumazenil has been reported to provoke panic attacks in patients with a history of panic disorders.

The following table summarizes the adverse reactions which occurred with an incidence of >1%.

Clinical Adverse Events >1%

Overdose

Other clinical adverse events which occurred with an incidence of <1% are as follows:

Cardiovascular

Ventricular premature beats, arrhythmia, palpitations, bradycardia, flush, hypotension, chest pain.

Respiratory

Dyspnea, hypopnea, nasal congestion, cough, subjective suffocation.

CNS/Neuromuscular

Startle reaction, fear, nervousness, restlessness, excitation, aggressiveness, anger, euphoria, hallucinations, vertigo, confusion, tiredness/drowsiness, depression, involuntary/spontaneous movement, tremor, mouth movement, tetany, speech disorder.

Gastrointestinal

Salivation, dry mouth, hiccoughs.

Dermatological

Urticaria, pruritus.

Miscellaneous

Pain, allergic reaction, strabismus, sweating.

Local Tolerance

Slight to moderate pain at the site of injection occurred in 2.5% of patients and redness was observed in 1.3% of patients in clinical trails one hour after the administration of flumazenil.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Flumazenil, administered intravenously to healthy volunteers at a dosage of 100 mg, did not produce symptoms of overdosage. Reversal of sedation or general anesthesia with excessively high doses of Flumazenil Injection SDZ may produce symptoms of benzodiazepine withdrawal, such as anxiety, agitation, increased muscle tone, hyperesthesia, and possible convulsions.

There is very limited experience of acute overdose in humans with flumazenil. There is no specific antidote for overdose with flumazenil. Treatment of an overdose with Flumazenil Injection SDZ should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Convulsions associated with the flumazenil administration have been successfully managed with benzodiazepines, phenytoin or barbiturates (see WARNINGS-Seizures).

DOSAGE AND ADMINISTRATION

FLUMAZENIL INJECTION SDZ SHOULD BE ADMINISTERED INTRAVENOUSLY BY A PHYSICIAN WITH EXPERIENCE IN ANESTHESIOLOGY.

Flumazenil Injection SDZ is not indicated for epileptic patients who have been treated with benzodiazepines for a prolonged period. The abrupt cessation of the protective effect of benzodiazepines may induce convulsions in epileptic patients.

Caution should be exercised with initial and repeated dosing to patients with hepatic insufficiency as elimination of flumazenil can be delayed in these patients (see ACTION AND CLINICAL PHARMACOLOGY-Hepatic Impairment).

The dose of Flumazenil Injection SDZ should always be individually titrated to the desired response to avoid abrupt awakening. Particular care is needed with patients who are physically dependent on benzodiazepines, patients who have ingested multiple drugs, and patients who are prone to anxiety. In the intensive care unit, in patients treated with high doses of benzodiazepines and/or for long periods of time, the individually titrated injections of Flumazenil Injection SDZ, slowly administered, should not produce withdrawal syndromes (see PRECAUTIONS). If unexpected symptoms occur, diazepam or midazolam could be carefully titrated intravenously according to patient’s response.

Flumazenil Injection SDZ may be used concurrently with other resuscitative procedures (see Known or Suspected Benzodiazepine Overdose).

Flumazenil Injection SDZ is compatible with 5% dextrose in water and normal saline solutions. If Flumazenil Injection SDZ is drawn into a syringe or mixed with any of these solutions, it should be discarded after 24 hours (see PHARMACEUTICAL INFORMATION).

Reversal of General Anesthesia/Sedation

The recommended initial dose is 0.2 mg administered intravenously over 15 seconds. If the desired level of consciousness is not obtained within 60 seconds, a further dose of 0.1 mg can be injected and repeated at 60 second intervals, up to a maximum total dose of 1 mg. The usual dose is between 0.3 and 0.6 mg.

Known or Suspected Benzodiazepine Overdose

Necessary measures should be taken to monitor the patient’s vital signs and institute supportive treatment as indicated by the patient’s clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. Flumazenil Injection SDZ is intended as an adjunct to, not as a substitute for, supportive measures used to manage overdose (e.g., proper management of airway, assisted breathing, circulatory access and support, internal decontamination by charcoal and possibly lavage, and adequate clinical evaluation).

For the reversal of excessive sedative effects of benzodiazepines in overdose cases, titrate flumazenil as described below, until the patient clearly responds or until the maximum recommended dose has been reached.

The recommended initial dose is 0.3 mg administered intravenously over 30 seconds, followed by a series of 0.3 mg injections, each administered over a 30-second period, at 60 second intervals. The maximum recommended dose is 2.0 mg.

If a significant improvement in the level of consciousness and respiratory function is not achieved after repeated injections of flumazenil, a non-benzodiazepine aetiology must be assumed.

If drowsiness recurs, an intravenous infusion of 0.1-0.4 mg/hr may be useful. The rate of the infusion should be individually adjusted to the desired level of arousal.

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Flumazenil

Code: Ro 15-1788

Chemical Names: (1) 4H-Imidazo[1,5-α][1,4]benzodiazepine-3-carboxylic acid,

8-fluoro-5,6-dihydro-5-methyl-6-oxo, ethyl ester

(2) Ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-α][1,4] benzodiazepine-3-carboxylate

Structural Formula:

N

N

O

O

CH₂CH₃

N

O CH3

F

Molecular Formula: C₁₅H₁₄FN₃O₃

Molecular Weight: 303.29 g/mol

Description: White or almost white crystalline powder

Solubility: Freely soluble in dichloromethane, sparingly soluble in methanol, slightly soluble in hydrochloric acid 0.1N and very slightly soluble in water.

Melting Range: 198-202ºC

pH: Flumazenil is very slightly soluble in water, therefore pH cannot be measured.

pKa: 1.7 (in weak base)

Composition

Each mL of Flumazenil Injection SDZ (Manufacturer’s Standard) contains: flumazenil 0.1 mg, sodium chloride for isotonicity, edetate disodium 0.1 mg, acetic acid 0.1 mg, sodium hydroxide to adjust pH and water for injection.

Stability and Storage Recommendations

Flumazenil Injection SDZ should be stored between 15°C - 30°C. Discard unused portion.

Stability and Storage of Diluted Solutions

Flumazenil Injection SDZ may be diluted with dextrose 5% solution or sodium chloride 0.9%. If flumazenil is drawn into a syringe or mixed with any of these solutions, it should be discarded after 24 hours.

AVAILABILITY OF DOSAGE FORMS

Flumazenil Injection SDZ 0.1 mg/mL is available in single use ampoules of 5 mL, boxes of 5.

PHARMACOLOGY

Receptor Studies

Using ³H-flumazenil, a benzodiazepine antagonist or ³H-clonazepam, a benzodiazepine agonist as radioligands in in vitro binding studies, a variety of receptor agonists showed very similar potency in inhibiting the binding of either ligand.

Flumazenil also displaced ³H-flunitrazepam under in vivo conditions. The ED₅₀ was 4.0 mg/kg PO when mice were sacrificed 15 minutes after the administration of flumazenil. Autoradiography studies have revealed that while ³H-flunitrazepam binds to both central and peripheral benzodiazepine receptor sites, ³H-flumazenil binds only to central receptor sites. This suggests that flumazenil will antagonize only those effects of the benzodiazepines that are mediated via the central nervous system.

While flumazenil interacts with the same number of benzodiazepine receptor sites as the benzodiazepines, the mode of interaction of the antagonist and agonists differs. Under conditions which alter receptor affinity for agonists, no change is seen in ³H-flumazenil binding. Specifically, (a) in the presence of GABA, benzodiazepine receptor affinity is enhanced for agonists, but remains unchanged for flumazenil; (b) in the presence of photoaffinity labelling, benzodiazepine receptor affinity is attenuated for agonists, but remains unchanged for flumazenil.

In conclusion, similar to benzodiazepine agonists, flumazenil interacts with central benzodiazepine receptors in nanomolar concentrations, the inhibition of agonist binding by flumazenil being competitive. Unlike the agonists, flumazenil is insensitive to GABA or photoaffinity labelling induced changes in receptor affinity.

Benzodiazepine Antagonist Activity

Flumazenil potently antagonizes the centrally-mediated pharmacological effects of various benzodiazepines. In the table below, only the minimal effective doses are described, but flumazenil exerts its effects in a dose-dependent fashion.

Antagonism of Benzodiazepines in Neurological and Behavioural Studies

The ability of flumazenil to antagonize benzodiazepine agonists is specific for this class of drugs. The muscle relaxant, anticonvulsant, and anti-conflict effects of phenobarbital, meprobamate, and ethanol were not antagonized by flumazenil. Flumazenil was also inactive against scopolamine or hypercapnia-induced anterograde amnesia and morphine-induced respiratory depression.

Flumazenil-Induced Withdrawal

Flumazenil, administered IV, IM, or PO, elicited typical benzodiazepine withdrawal signs in mice, rats, cats and squirrel monkeys, following chronic administration of benzodiazepines (12 to 35 days). The symptoms included emesis, vocalization, tremors, rigidity, and convulsions. The type of withdrawal symptoms and their intensity depended upon the dose and duration of benzodiazepine treatment, as well as the time of flumazenil administration vis-à-vis the last dose of the benzodiazepine.

Intrinsic Activity

Flumazenil did not affect normal behaviour in rats, dogs, or squirrel monkeys in doses of up to 100 mg/kg. Similarly, motor activity, conditioned avoidance behaviour, conflict behaviour in rats and continuous avoidance behaviour in squirrel monkeys remained unchanged when flumazenil was given in doses of up to 100 mg/kg PO. These findings indicate that flumazenil is devoid of benzodiazepine agonist activity at doses that are substantially higher than those which exert antagonist activity.

Inverse Agonist Activity

A group of benzodiazepine receptor ligands, classified as “inverse agonists” cause opposite effects to those of the benzodiazepine receptor agonists, namely they produce convulsions and anxiety in appropriate animal models.

Flumazenil did not induce convulsions, except at sublethal doses. However, it did exert weak anxiogenic activity in several behavioural animal models, namely in the “social interaction” and “conditioned spatial aversion” tests, as well as in various conflict situations. Active doses ranged from 4 to 30 mg/kg IP or PO.

Cardiovascular Effects

Flumazenil did not affect blood pressure or heart rate either in spontaneously-hypertensive rats (maximum dose 100 mg/kg PO) or in renal hypertensive dogs (maximum dose 30 mg/kg PO).

TOXICOLOGY

Acute Toxicity

Intravenous Pyramiding Dose Toxicity in Dogs

Three groups of four dogs each (2/sex) received (a) flumazenil at doses of 0.01, 0.03, 0.1 and 0.3 mg/kg; (b) pyramiding doses of the vehicle (0.1, 0.3, 1.0 and 3.0 mL/kg) and; (c) equivalent volumes of physiological saline. The dogs were dosed twice a week over a two-week period. All dogs survived the pyramiding doses of flumazenil and were essentially asymptomatic throughout the study. Flumazenil did not affect body weight, food intake, hematological or clinical chemical parameters.

Long-Term Toxicity Studies

1. 1.

   Two-Week Intravenous–Rats

   Flumazenil was injected IV into the tail vein of rats (8/sex/group) at doses of 0, 1, 3 and 10 mg/kg/day.

   Tissue irritation at the injection site was pronounced and dose-related. At the low dose, local tolerance was acceptable. At the mid-dose, all rats had swollen and reddened tails beginning with the third dose and continuing to the end of the study. At the high dose, intolerance at the injection site was severe. Hematomas occurred in five of eight males and one female rat. Two of eight male rats in the high-dose group also showed ulceration of the tail and in three male rats the administration of the drug had to be performed intraperitoneally on the fifth day. In general, female rats tolerated the treatment better than male animals. Pronounced bleeding at the injection site was also observed in most of the mid- and high-dose animals beginning about the fifth day of the study.

   At the 10 mg/kg dose, male rats gained weight at a slower rate than male controls, this effect was considered to be treatment-related. A similar effect in female rats was equivocal.

2. 2.

   Two-Week Oral–Rats

   Flumazenil was administered by gavage to rats (8/sex/group) at doses of 0, 5, 25 and 150 mg/kg/day. The drug was given for 15 or 16 consecutive days to female and male rats, respectively.

   Flumazenil was devoid of toxic effects at the doses studied.

3. 3.

   Two-Week Intravenous–Dogs

   Flumazenil was injected IV to beagle dogs (2/sex/group) at doses of 0, 1, 3 and 10 mg/kg/day.

   The mid-dose produced drowsiness and the high-dose produced drowsiness and ataxia; both effects were observed following dosing. In the course of the study, a slight tolerance did develop to these effects.

   Injections were poorly tolerated in the dogs receiving 10 mg/kg of flumazenil, due to hardened and thrombosed veins and a strong defence reaction from the animals.

   In the high-dose group, reticulocytes were significantly increased in the second week of the study in comparison to the control group. Platelets were decreased in all treated groups vis-à-vis baseline values, but the changes were not dose-related. A statistically significant increase in the relative liver weights was noted in the high-dose group, this effect was considered to be treatment-related.

4. 4.

   Two-Week Oral–Dogs

   Flumazenil was administered in capsules to beagle dogs (2/sex/group) at doses of 0, 5, 20 and 80 mg/kg/day for 15 consecutive days.

   Slight diarrhea was noted at the 20 mg/kg dose and marked diarrhea (sometimes bloody) at the 80 mg/kg dose. Mean spleen weights were decreased and mean liver weights increased in all flumazenil-treated dogs. At necropsy, the tunica mucosa of the colon was more convoluted in high-dose animals than in controls.

5. 5.

   Four-Week Intravenous–Rats

   Flumazenil was injected IV into the tail vein of rats (12/sex/group) at doses of 0, 1, 3 and 10 mg/kg/day.

   Local tolerance to the IV injections was poor and the degree of swelling and pain was dose-related. At the high dose, the route of administration had to be switched from intravenous to intraperitoneal about 15 days after the beginning of the study.

   In male rats, there was a dose-related weight gain deficit. Although the mean values remained within the normal range, WBC counts decreased in male rats in a dose-related fashion at week 4. The decrease seen in the high-dose group was statistically significant. Both absolute and relative liver weights were increased in high-dose female rats. Perilymphadenitis was seen in high-dose males and females; this might have been due to the intraperitoneal injections. One high-dose female rat had a moderate degenerative change in the retina.

6. 6.

   Four-Week Intravenous–Dogs

   Flumazenil was injected IV to beagle dogs (2/sex/group) at doses of 0, 1, 3 and 10 mg/kg/day.

   Mid-dose dogs were sedated and high-dose dogs showed both sedation and ataxia. Tolerance did not develop to these effects. WBC counts decreased slightly. While the mean values were within normal range, in a few dogs they fell below normal. Local tolerance (injection site) was poor in the high-dose groups as also shown by high inflammation scores.

7. 7.

   Thirteen-Week Oral–Rats

   Flumazenil was administered in the diet to rats (18/sex/group) at doses of 0, 5, 25 and 125 mg/kg/day.

   In female rats, liver weights were somewhat elevated in the high-dose group, and thyroid weights slightly decreased in a dose-related fashion.

8. 8.

   Thirteen-Week Oral–Dogs

   Flumazenil was administered in capsules to beagle dogs, (3/sex/group), seven days/week, at doses of 0, 5, 20 and 80 mg/kg/day.

   Slight sedation, lasting 1-3 hours following dosing was noted in the high-dose group; tolerance did not develop to this effect. Weight gain in high-dose animals was somewhat attenuated when compared to controls. At week 12, heart rate was increased in high-dose dogs, vis-à-vis both baseline and control dogs. There was a dose-related decrease in both absolute and relative spleen weights.

9. 9.

   Twelve-Month Oral–Rats

   Flumazenil was administered in the diet to rats (20-30/sex/group) at doses of 0, 6, 20 and 125 mg/kg/day. An interim sacrifice of ten control rats (5/sex) and ten rats from the high-dose group (5/sex) was carried out at six months.

   Hemoglobin, erythrocyte and hematocrit values were slightly lower in treated male animals than in controls, throughout the study. In females, these parameters were reduced only at six months.

   At six months, both absolute and relative thyroid weights in high-dose males, and liver weights in high-dose females were significantly increased. Histopathological evaluation revealed a slight to moderate congestion in the liver of all females treated with the high dose. At twelve months, absolute and relative thyroid weights were slightly decreased in low- and mid-dose males, but increased in high-dose animals. Liver weights and histopathological findings were similar in treated and control rats.

Mutagenicity

Flumazenil had no mutagenic activity in six out of seven mutagenicity assays (Ames test, Treat and Plate test, gene mutation, in vivo and in vitro clastogenicity and in vivo DNA repair). In a UDS assay, there was a dose-dependent unscheduled incorporation of ³H-thymidine in nuclear DNA of rat hepatocytes after treatment with flumazenil concentrations of 252, 504 and 1010 mcg/mL for eighteen hours. However, the increase could only be shown at substance concentrations that were also cytotoxic. Since there were no effects in the absence of cytotoxicity, interactions between cytotoxic and DNA-damaging effects, resulting in repair processes, cannot be excluded.

Reproduction and Teratology

1. 1.

   Fertility and General Reproductive Performance

   In a Segment I study, flumazenil was administered by gavage to rats in doses of 0, 15, 45 and 125 mg/kg/day. Thirty-two males per group were treated for 10 weeks prior to mating and during the mating period. The treatment of 32 females per group started two weeks prior to mating and continued through the gestation and lactation periods. No mortality or adverse effects were observed on parental animals.

   Mating success, gestation length and outcome of pregnancy was not influenced by treatment either in the parental or in the F1 generation.

   Gestational parameters such as the number of corpora lutea, implantations, resorptions and number of pups born alive were comparable to concurrent and historical control data in the parental as well as in the F1 generation.

   Weight gain of F1-pups was normal in the low- and mid-dose groups but slightly decreased in the high-dose group. This decrease became statistically significant at weaning (lactation day 23). The viability of pups from the F1 and F2 generation was not affected by treatment.

2. 2.

   Teratology–Rats

   In a Segment II study, flumazenil was administered by gavage to rats at doses of 0, 15, 50 and 150 mg/kg/day. The test drug was administered to 40 mated female rats/dose from day 7 to day 16 of gestation inclusively; control rats received a similar volume of the vehicle. The study included rearing of the offspring until weaning in order to determine the postnatal effects of prenatally administered flumazenil.

   Weight gain by the dams was not impaired and there was no evidence for an adverse effect on the various reproductive parameters (i.e. resorption rate, number of dead fetuses, mean body weight of fetuses, mean crown/rump length and duration of the gestation period). During the postnatal period, the body weight of pups increased uniformly in all dose groups and the incidence of pup mortality was not increased in any of the treatment groups.

   External, skeletal, and soft tissue examinations of the fetuses gave no indication of treatment-related teratogenicity. Five fetuses from a single litter in the high-dose group showed multiple skeletal abnormalities (i.e. shortened, poorly ossified and deformed long bones in fore and hind limbs, missing toes and enlarged heads).

3. 3.

   Teratology–Rabbits

   In a Segment II study, flumazenil was administered by gavage to rabbits at doses of 0, 15, 50 and 150 mg/kg/day. The test drug was administered to 20 mated female rabbits/dose from day 7 to day 19 of gestation, inclusively; control rabbits received a similar volume of the vehicle. Weight gain of the does during the gestation period, mating success, mean number of corpora lutea and mean number of implantations were not impaired in any of the groups. The resorption rate noted in the high-dose group (1.6 per pregnant female), was significantly greater than that for the concurrent control (0.7 per pregnant female), but was within the range for historical controls. Examinations of fetuses for malformations revealed no evidence for a teratogenic effect of flumazenil up to a dose of 150 mg/kg/day.

4. 4.

   Perinatal and Postnatal–Rats

   In a Segment III study, flumazenil was administered by gavage to rats at doses of 0, 5, 25 and 125 mg/kg. The test drug was administered to 24 mated females/group from day 16 of gestation until weaning, on day 22 of lactation. A control group received the vehicle.

   There were no significant dose or drug-related differences between the groups in the number of intrauterine and perinatal deaths. Mortality during lactation was increased in the high-dose group (14% versus 7.8% in the control group). From the weanlings in which the organs were weighed, a slight but dose-related increase of liver weights was noted in the mid- and high-dose groups. The physical and functional development of neonates was normal, although there was a slight but statistically significant delay of incisor eruption, ear opening and auditory startle response in the offsprings of high-dose-treated dams.

Irritation Studies

1. 1.

   Venous Irritation–Rabbits

   A single injection of 1.0 mL of flumazenil (1 mg/mL, mixed micelles formulation) into the marginal ear vein of 6 New Zealand rabbits did not cause significant irritation of the veins.

2. 2.

   Local Tolerance–Rabbits

   Five rabbits were given an IV injection of 0.5 mL of flumazenil (0.5 mg/5 mL, aqueous formulation) in the direction of the venous flow for the marginal ear veins. IV tolerance was rated as good; only one animal had some reddening in the vicinity of the injection site (without any effect on the vein) on days 1 and 2.

3. 3.

   Local Tolerance–Rat Hindquarter Muscle

   Intramuscular tolerance was rated as good in 10 rats receiving 0.1 mL of flumazenil (0.5 mg/5mL, aqueous formulation) into the gastrocnemius muscle of each hind limb. Creatinine phosphokinase was elevated relative to baseline at 24 hours after injection in both treated and control animals. The elevations seen in treated rats were somewhat larger than those observed in the control group.

4. 4.

   Hemolysis Testing–Dogs

   Intravenous administration of 1.0 mL of flumazenil (1 mg/mL, mixed micelles formulation) to 12 dogs did not produce any significant hemolysis.

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