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Overview Of Diazepam Vaginal Suppository

Diazepam is an oral, nasal, parenteral, or rectal long-acting benzodiazepine indicated for anxiety, acute alcohol withdrawal, skeletal muscle spasm, and seizure disorders, including status epilepticus. Diazepam may be used adjunctively for skeletal muscle spasms and seizure disorders; it has not been proven useful as sole therapy in epilepsy. As an adjunct or premedication before procedures like surgery or endoscopy, diazepam may relieve apprehension or acute stress and diminish patient recall of the procedure. Like with other benzodiazepines, concomitant use of diazepam with opioids may result in profound sedation, respiratory depression, coma, and death.
Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the CNS and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, and anticonvulsant activity. Recent evidence indicates that benzodiazepines exert their effects through enhancement of the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes designated GABA-A and GABA-B. GABA-A is the primary receptor subtype in the CNS and is thought to be involved in the actions of anxiolytics and sedatives.
Specific benzodiazepine receptor subtypes are thought to be coupled to GABA-A receptors. Three types of BNZ receptors are located in the CNS and other tissues; the BNZ1 receptors are located in the cerebellum and cerebral cortex, the BNZ2 receptors in the cerebral cortex and spinal cord, and the BNZ3 receptors in peripheral tissues. Activation of the BNZ1 receptor is thought to mediate sleep while the BNZ2 receptor affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. Benzodiazepines bind nonspecifically to BNZ1 and BNZ2 which ultimately enhances the effects of GABA. Unlike barbiturates which augment GABA responses by increasing the length of time that chloride channels are open, benzodiazepines enhance the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.
The antianxiety action of benzodiazepines may be a result of their ability to block cortical and limbic arousal following stimulation of the reticular pathways while muscle relaxation properties are mediated by inhibiting both mono- and polysynaptic pathways. Benzodiazepine can also depress muscle and motor nerve function directly. Animal studies of the anticonvulsant actions suggest that benzodiazepines augment presynaptic inhibition of neurons, thereby limiting the spread of electrical activity, although they do not actually inhibit the abnormally discharging focus. Benzodiazepines alleviate insomnia by decreasing the latency to sleep and increasing sleep continuity and total sleep time through their effects on GABA.
Benzodiazepines may also have other actions. For example, diazepam has been shown to counteract the cardiovascular toxicity of chloroquine. It is thought that diazepam increases the urinary clearance of chloroquine by improving electrocardiographic and hemodynamic function.
Diazepam is administered orally, nasally, parenterally, and rectally. Both diazepam and its major active metabolite, desmethyldiazepam, bind extensively to plasma proteins (95% to 98%). Diazepam and its metabolite cross the blood-brain barrier. In young healthy males, the volume of distribution at steady-state is 0.8 to 1 L/kg. Metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. Diazepam is extensively metabolized to 1 major active metabolite, desmethyldiazepam, and 2 minor active metabolites, temazepam (3-hydroxydiazepam) and oxazepam (3-hydroxy-N-diazepam). At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam while oxazepam and temazepam are usually undetectable. The initial distribution phase is followed by a prolonged terminal elimination phase (half-life up to 48 hours). The terminal elimination half-life of N-desmethyldiazepam is up to 100 hours. Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates. The clearance of diazepam is 20 to 30 mL/minute in young adults. Diazepam accumulates upon multiple dosing, and there is some evidence that the terminal elimination half-life is slightly prolonged. The marked interindividual variability in the clearance of diazepam is probably attributable to variability of CYP2C19, which is known to exhibit genetic polymorphism, and CYP3A4.
Diazepam is contraindicated in any patient with a known hypersensitivity to diazepam.
Monitor all patients beginning treatment with antiepileptic drugs (AEDs) or currently receiving diazepam closely for emerging or worsening depression or suicidal ideation. Advise patients and caregivers of the increased risk of suicidal thoughts and behaviors and to immediately report the emergence of new or worsening of depression, suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any patient may be related to the illness being treated. There is an increased risk of suicidal ideation and behavior in patients receiving AEDs to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years of age and older). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Diazepam is not recommended in the treatment of psychosis; do not use diazepam instead of appropriate treatment.
Chronic diazepam use, even at therapeutic doses, may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena. Consequently, after extended therapy, avoid abrupt discontinuation and follow a gradual dosage tapering schedule.
Benzodiazepines, including diazepam, may produce CNS depression. Advise patients against engaging in hazardous activities requiring mental alertness (e.g., driving or operating machinery or riding a bicycle) until the effects of the drug, such as drowsiness, have subsided, and their medical condition permits. Advise patients against simultaneous ethanol ingestion or ethanol intoxication as well as ingestion of other CNS depressant drugs during diazepam therapy. Do not administer diazepam injection to patients in coma or shock.
Diazepam is contraindicated in patients with closed-angle glaucoma. It may be used in patients with open-angle glaucoma who are receiving appropriate therapy. Benzodiazepines, including diazepam, can increase intraocular pressure in patients with glaucoma.
Diazepam metabolites are excreted by the kidneys; to avoid their excess accumulation, use caution when administering diazepam to patients with renal disease, including renal impairment or renal failure.
Use diazepam with caution in the geriatric adult, especially for chronic treatment. Significant accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted in elderly subjects receiving prolonged, routine therapy. Decreased elimination may also occur in some elderly patients due to a decline in renal function and can either intensify or prolong the adverse reactions of the drug. The impairment of cognitive and motor function may be more marked in this patient group. Because diazepam can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries. Due to its long half-life and the availability of safer alternatives, diazepam is not recommended for the treatment of insomnia in the elderly. In geriatric and debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation and that close monitoring be employed. Use caution when administering diazepam intravenously to the elderly due to the risk of apnea and/or cardiac instability. According to the Beers Criteria, benzodiazepines are considered potentially inappropriate medications (PIMs) in geriatric patients and avoidance is generally recommended, although some agents may be appropriate for seizure disorders, rapid eye movement sleep disorders, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, or peri-procedural anesthesia. Older adults have an increased sensitivity to benzodiazepines and slower metabolism of long-acting agents, which increases their risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents. The Beers panel recommends avoiding benzodiazepines in geriatric patients with the following conditions due to the potential for symptom exacerbation or adverse effects: delirium (new-onset or worsening delirium), dementia (adverse CNS effects), and history of falls/fractures (ataxia, impaired psychomotor function, syncope, and additional falls). If a benzodiazepine must be used in a patient with a history of falls or fractures, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The Beers criteria are not meant to apply to patients at the end of life or receiving palliative care, when risk-benefit considerations of drug therapy can be different. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). Specific criteria for anxiolytics must be met, including 1) limiting use to indications specified in the OBRA guidelines (e.g., generalized anxiety disorder, panic disorder, significant anxiety to a situational trigger, alcohol withdrawal) which meet the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for the indication, and 2) evidence exists that other possible reasons for the individual’s distress have been considered, and 3) use results in maintenance or improvement in mental, physical, and psychosocial well-being as reflected on the Minimum Data Set (MDS) or other assessment tool. Anxiolytics should be used for delirium, dementia, or other cognitive disorders only when there are associated behaviors that are 1) quantitatively and objectively documented, and 2) are persistent, and 3) are not due to preventable or correctable reasons, and 4) constitute clinically significant distress or dysfunction to the LTCF resident or represent a danger to the resident or others. There are exceptions that may warrant the use of an anxiolytic such as a long-acting benzodiazepine for withdrawal from a short-acting benzodiazepine, use for neuromuscular syndromes (e.g., tardive dyskinesia, restless legs syndrome, seizure disorder, cerebral palsy), or end of life care. The need for indefinite continuation of diazepam (e.g., seizure disorder) should be based on confirmation of the condition being treated and its potential cause(s). It should be noted that benzodiazepines may increase the risk of confusion, sedation, and falls. OBRA provides dosing guidance for diazepam as an anxiolytic. When a medication is used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.
There are no adequate data on diazepam use during human pregnancy. Consider diazepam use during pregnancy only when the clinical situation warrants the risk to the fetus. If diazepam is to be used during pregnancy or the patient becomes pregnant while taking diazepam, advise the patient of the potential hazard to the fetus. Measurable amounts of diazepam were found in cord blood, indicating placental transfer of the drug. Available data suggest that the class of benzodiazepines is not associated with marked increases in risk for congenital anomalies. A meta-analysis of 23 studies examined the effects of benzodiazepine exposure during the first trimester of pregnancy. Eleven of the 23 studies included in the meta-analysis considered the use of chlordiazepoxide and diazepam and not other benzodiazepines. Case-control and cohort studies were considered separately. The data from the cohort studies did not suggest an increased risk for major malformations (OR 0.90; 95% CI 0.61 to 1.35) or oral cleft (OR 1.19; 95% CI 0.34 to 4.15). The data from the case-control studies suggested an association between benzodiazepines and major malformations (OR 3.01, 95% CI 1.32 to 6.84) and oral cleft (OR 1.79; 95% CI 1.13 to 2.82). The limitations of this meta-analysis included the small number of reports included in the analysis, and that most cases for analyses of both oral cleft and major malformations came from only 3 studies. A follow up to that meta-analysis included 3 new cohort studies that examined risk for major malformations and 1 study that considered cardiac malformations. No new studies with an outcome of oral clefts were found. After the addition of the new studies, the odds ratio for major malformations with first trimester exposure to benzodiazepines was 1.07 (95% CI 0.91 to 1.25). There is insufficient evidence to assess the effect of benzodiazepine pregnancy exposure on neurodevelopment. In animal studies, administration of diazepam during the organogenesis period of pregnancy resulted in increased incidences of fetal malformations at doses greater than those used clinically. Data for diazepam and other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings in animals after prenatal or early postnatal exposure at clinically relevant doses. Clinical considerations regarding exposure to benzodiazepines during the second and third trimesters of pregnancy and immediately before or during labor and obstetric delivery include decreased fetal movement and/or fetal heart rate variability, floppy infant syndrome, dependence, and withdrawal. Neonatal withdrawal syndrome and symptoms suggestive of floppy infant syndrome associated with administration of benzodiazepines during the later stages of pregnancy and peripartum have been reported. Clinical manifestations of withdrawal or neonatal abstinence syndrome may include hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, and vomiting. These complications can appear shortly after birth to 3 weeks after birth and persist from hours to several months, depending on the degree of dependence and the pharmacokinetic profile of the benzodiazepine. Symptoms may be mild and transient or severe. Standard management for neonatal withdrawal syndrome has not yet been defined. Floppy infant syndrome is characterized by lethargy, hypothermia, hypotonia, respiratory depression, and difficulty feeding. Floppy infant syndrome occurs mainly within the first hours after birth and may last up to 14 days. Observe newborns who are exposed to diazepam for symptoms of withdrawal and floppy infant syndrome and manage accordingly. The major neonatal side effects of benzodiazepines also include sedation. Data suggest that fetal exposure to benzodiazepines is also associated with the neonatal adverse events of hypotonia, respiratory problems, hypoventilation, and low Apgar score. To monitor human fetal outcomes, pregnant women taking diazepam are encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Patients must enroll themselves by calling the registry at 1-888-233-2334 or visiting www.aedpregnancyregistry.org.
Breast-feeding is not recommended in patients receiving oral diazepam. Because diazepam and its metabolites may be present in human breast milk for a prolonged period after acute use of rectal diazepam, advise patients not to breast-feed for an appropriate period of time after receiving rectal diazepam. Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for nasal diazepam and any potential adverse effects on the breast-fed infant from diazepam or the underlying maternal condition. Diazepam is excreted in human milk. There are no data to assess the effects of diazepam on milk production. Postmarketing experience suggests that breast-fed infants of mothers taking benzodiazepines may have effects of lethargy, somnolence, and poor sucking. Diazepam concentrations were assessed in 3 breast-feeding mothers receiving diazepam 30 mg daily for 6 days after delivery. The mean concentration of diazepam and its metabolite in the mothers’ sera, the breast milk, and the infants’ sera at 4 days were 831 ng/mL, 79 ng/mL, and 415 ng/mL and at 6 days were 1,084 ng/mL, 130 ng/mL, and 105 ng/mL, respectively. The infants’ mean serum concentration decrease from days 4 to 6 may be due to decreases in the amount of milk consumed or the onset of elimination mechanisms. None of the infants showed signs of lethargy or hypoventilation. An infant exposed to diazepam 30 mg daily at 5 days postpartum experienced weight loss, lethargy, and electroencephalogram (EEG) findings consistent with sedative medication. A small series of 9 infants exposed to diazepam at unspecified doses through breast milk found the only adverse event was mild jaundice in 3 of the infants. Previous American Academy of Pediatrics recommendations considered diazepam as a drug whose effect on the breast-feeding infant is not known but may be of concern, particularly with prolonged exposure. If occasional maternal therapy with a benzodiazepine is required, lorazepam or oxazepam may be reasonable alternatives for some patients. Some experts suggest that occasional maternal treatment with usual doses of lorazepam or oxazepam would pose little risk to a breast-feeding infant.
Tolerance or tachyphylaxis may develop to the sedative effects of benzodiazepines, including diazepam. Tolerance to the anxiolytic effects of benzodiazepines has also been reported. If tolerance develops, carefully assess the need for escalating doses. In some cases, a temporary reduction in dosage may be beneficial to reverse the effects of tachyphylaxis.
Prolonged use of benzodiazepines such as diazepam can produce physiological dependence with or without psychological dependence. The risk of dependence increases with duration of treatment and in those with a history of alcohol or drug abuse. Dependence can occur after routine use of therapeutic doses for as few as 1 to 2 weeks, particularly during treatment with short-acting benzodiazepines. Extreme caution is advised when considering the use of benzodiazepines in patients with a known or suspected history of substance abuse.
Anterograde amnesia can occur after administration of therapeutic doses of benzodiazepines, such as diazepam. The risk for developing anterograde amnesia increases at higher doses and with concurrent ingestion of alcohol.
Most of the adverse effects associated with diazepam therapy are dose-dependent and CNS-related including headache, drowsiness, ataxia, dizziness, confusion, depression, syncope, fatigue, tremor, and vertigo. Tolerance may develop to these effects. Children and the elderly may be more susceptible to the CNS effects of benzodiazepines. During a placebo-controlled study comparing the effectiveness of oral diazepam to alprazolam in the treatment of panic disorder, the following CNS effects and incidences were reported in the diazepam group, alprazolam group, and placebo group, respectively: drowsiness (84%, 76.6%, 41.6%), fatigue (56.8%, 44.2%, 41.6%), impaired thinking (44.4%, 37.7%, 22.1%), memory impairment (39.5%, 33.8%, 31.2%), and imbalance/incoordination (55.6%, 40.3%, 16.9%); similar incidences of side effects may occur with use of diazepam for other indications, such as anxiety. CNS adverse events occurring in controlled clinical trials of diazepam rectal gel at a greater frequency than placebo included drowsiness (23%), headache (2% to 5%), dizziness (2% to 5%), ataxia (2% to 5%), and incoordination (2% to 5%). CNS adverse events occurring in at least 1% of patients in clinical trials of diazepam rectal gel include nervousness, confusion, emotional lability, thinking abnormal, and vertigo. Because diazepam can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries. There have been reports of falls and bone fractures in benzodiazepine users; these risks are increased during concurrent use of sedatives and in the elderly.
During a placebo-controlled study comparing the effectiveness of oral diazepam to alprazolam in the treatment of panic disorder, the following effects and incidences were reported in the diazepam group, alprazolam group, and placebo group, respectively: dysarthria (32.1%, 23.4%, 5.2%) and urinary incontinence or urinary retention (17.3%, 15.6%, 10.4%). In controlled clinical trials of diazepam rectal gel, rash (unspecified) occurred in 2% to 5% of patients. Dysarthria and speech disorder were reported in at least 1% of patients receiving diazepam rectal gel in clinical trials; pruritus and mydriasis were reported in less than 1% of patients. Blurred vision, diplopia, nystagmus, urticaria, and skin reactions (unspecified) have been reported during treatment with diazepam. The frequencies of these events are unknown.
Elevated hepatic enzymes (e.g., transaminases, alkaline phosphatase) have been reported during diazepam administration. Monitor periodic blood counts and liver function tests during chronic treatment due to rare reports of neutropenia and jaundice. Anemia was reported in less than 1% of patients receiving diazepam rectal gel in clinical trials.
Paradoxical CNS stimulation has been reported with benzodiazepine use and is of particular significance in children and the elderly. This paradoxical effect is possibly due to release of previously inhibited responses. Symptoms of CNS stimulation include nightmares, talkativeness, excitement, mania, tremor, insomnia or other sleep disturbances, anxiety, agitation, aggressiveness, irritability, hallucinations, delusions, restlessness, euphoria, acute rage reactions, and hyperactivity. Discontinue benzodiazepine therapy if signs of CNS stimulation occur. Euphoria occurred in 3% of patients in controlled clinical trials of diazepam rectal gel compared to none of the patients receiving placebo. Agitation was also reported in at least 1% of patients receiving diazepam rectal gel in clinical trials.
Muscle weakness (myasthenia) is among the most commonly reported side effects of diazepam, although the incidence of this side effect associated with dosage forms other than the rectal gel (1% or more) is unknown. Apnea, hypotension, and cardiac arrest have been reported after parenteral administration of benzodiazepines to the elderly, severely ill patients, or patients with compromised respiratory function. Hypotension has also been reported with other diazepam formulations and occurred in 1% or more of patients who received the rectal gel in clinical trials. Cardiovascular collapse and bradycardia have been reported with diazepam injection and the rectal gel (1% or more). Respiratory depression also has occurred in susceptible patients during benzodiazepine therapy, occasionally resulting in death; respiratory depression can also occur with overdosage. A prospective study evaluated the incidence of respiratory depression in children with seizures treated with rectal and/or intravenous diazepam in the emergency room setting. The median dose of rectal diazepam administered was 0.27 mg/kg (range: 0.14 to 0.74 mg/kg) and the median dose of IV diazepam was 0.16 mg/kg (range: 0.08 to 0.4 mg/kg). In 122 patients episodes, 94 children received diazepam, and 11 of these episodes resulted in respiratory depression (9%). Depressed respiration, dyspnea, hyperventilation, laryngospasm, throat pain, and chest pain (unspecified) have been reported with parenteral diazepam administration during peroral endoscopic procedures however, some of these effects may be related to the procedure performed instead of the drug. Peripheral vasodilation occurred in 1% to 5% of patients receiving diazepam rectal gel in controlled clinical trials compared to none of the patients receiving placebo. Hyperkinesis was reported in less than 1% of patients.
Abrupt discontinuation of diazepam after prolonged use can cause seizures in susceptible patients. Benzodiazepine withdrawal causes irritability, nervousness, and insomnia. Benzodiazepine withdrawal is more likely to occur after abrupt cessation after excessive or prolonged doses, but it can occur after the discontinuance of therapeutic doses administered for as few as 1 to 2 weeks. Benzodiazepine withdrawal is also more severe if the agent involved has a relative shorter duration of action. Abdominal cramps, confusion, depression, perceptual disturbances, sweating, nausea, vomiting, paresthesias, photophobia, hyperacusis, tachycardia, and trembling also occur during benzodiazepine whdrawal, but the incidence is less frequent. Convulsions, hallucinations, delirium, and paranoia can occur as well. Withdraw benzodiazepines cautiously and gradually, using a dosage-tapering schedule. Diazepam is usually chosen as the agent for controlled tapering in all cases of benzodiazepine withdrawal.
Changes in libido have been reported with the use of diazepam for chronic conditions. During one placebo-controlled study comparing the effectiveness of oral diazepam to alprazolam in the treatment of panic disorder, the following effects and incidences were reported in the diazepam group, alprazolam group, and placebo group, respectively: libido decrease (18.5%, 13%, 5.2%), libido increase (18.5%, 7.8%, 3.9%), unspecified sexual dysfunction (7.4%, 2.6%, 1.3%), and also menstrual irregularity (18.4%, 12.2%, 5.5%).
Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.
You can order Diazepam Vaginal Suppository from MediLab’s compounding pharmacy in the following Florida regions:
North Florida South Florida
Jacksonville Miami West Palm Beach Weston
Pensacola Hialeah Pompano Beach Delray Beach
Tallahassee Fort Lauderdale Davie Homestead
Ocala Port St. Lucie Miami Beach Tamarac
Gainesville Pembroke Pines Plantation Sarasota
Fort Walton Beach Hollywood Sunrise Wellington
Panama City Miramar Boca Raton Jupiter
Palm Coast Coral Springs Deerfield Beach Margate
Dunnellon Miami Gardens Boynton Beach Coconut Creek
Naples Lauderhill Broward
Spring hill Orlando
 
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