vSoothe 2 Vaginal Cream

Cyclobenzaprine

Cyclobenzaprine is a skeletal muscle relaxant approved for the relief of muscle spasm associated with acute, painful musculoskeletal conditions. Cyclobenzaprine is not effective for the treatment of muscle spasm due to central nervous system disease (e.g., cerebral palsy, spinal cord disease). Cyclobenzaprine is very closely related to the antidepressant amitriptyline. Although it is not used clinically as an antidepressant, cyclobenzaprine does possess some pharmacologic effects similar to tricyclic antidepressants. Flexeril® (cyclobenzaprine 10 mg) was first app

Gabapentin is an analog of gamma-aminobutyric acid (GABA) that has GABA agonist activity. Its unique pharmacokinetic properties make it especially useful in certain patients. Gabapentin possesses high lipid solubility, is not metabolized by the liver, has no protein binding, and is devoid of enzyme induction-related drug interactions. Originally developed as an anticonvulsant, gabapentin has been shown to be effective as adjunct therapy in the treatment of partial seizures with or without secondary generalized tonic-clonic seizures. Efficacy in the treatment of painful neuropathies has also been demonstrated. Investigational uses include monotherapy of refractory partial seizure disorders, treatment of spasticity in multiple sclerosis, and tremor. In addition, gabapentin appears to be effective in reducing hot flashes in menopausal women or women with breast cancer.

Ketamine

Ketamine is a general anesthetic indicated as the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation, for the induction of anesthesia before the administration of other anesthetic agents, and as a supplement to other anesthetic agents. It is also used for acute agitation and treatment of acute or chronic pain. Ketamine is unique sedative-hypnotic that produces dissociative anesthesia characterized by potent sedation, amnesia, and analgesia while maintaining cardiovascular stability and preserving spontaneous respiration and protective airway reflexes. It is similar in structure, mechanism of action, and activity to phencyclidine (PCP), but ketamine is much less potent and has a shorter duration of action. Ketamine has bronchodilatory properties and, in comparison to other sedatives (e.g., opioids, benzodiazepines), offers the advantage of fewer adverse reactions. Hence, ketamine may be an effective alternative to conventional intensive care sedation in certain clinical scenarios (e.g., patients who develop adverse cardiovascular effects with opioids or benzodiazepines, sedation with preservation of spontaneous ventilation, patients with refractory bronchospasm or status asthmaticus). Ketamine is a sympathomimetic; elevations in heart rate and blood pressure are often mild-to-moderate, but it should not be used in patients in whom significant elevations would be deleterious. Ketamine anesthesia is notorious for producing a cataleptic state where the eyes remain open with nystagmus; this “disconnected” state may be disconcerting to caregivers and warrants proper caregiver preparation. Other prominent effects of ketamine include excessive airway secretion and emergence reactions. The latter can be managed with short-acting benzodiazepines or barbiturates.

Lidocaine

Lidocaine is a widely used antiarrhythmic and amide-type local anesthetic. As an anesthetic agent, it is available as an ointment, jelly, patch, or aerosol for topical use, as an oral solution, and as an injection. Lidocaine is classified as a class Ib antiarrhythmic. It may be considered for ventricular fibrillation (VF) and pulseless ventricular tachycardia (pVT) that is unresponsive to cardiopulmonary resuscitation (CPR), defibrillation, and vasopressor therapy. Evidence is inadequate regarding the routine use of lidocaine after cardiac arrest or early (within the first hour) after return of spontaneous circulation (ROSC). However, prophylactic use of lidocaine may be considered in certain circumstances (e.g., during emergency medical services transport) when treatment of recurrent VF/pVT may be challenging. Due to the potential for serious adverse reactions, including cardiovascular depression, continuous electrocardiogram monitoring is recommended during intravenous lidocaine treatment. There is limited evidence suggesting that nebulized lidocaine exhibits steroid-sparing effects when used in corticosteroid-dependent asthmatics. However, extreme caution is recommended until long-term safety and efficacy can be established.

Cyclobenzaprine

Since cyclobenzaprine is so closely similar to amitriptyline in chemical structure, some of its effects are similar to the tricyclic antidepressants, including anticholinergic activity, potentiation of norepinephrine, and antagonism of reserpine. Cyclobenzaprine relieves muscle spasms through a central action, possibly at the brain stem level, with no direct action on the neuromuscular junction or the muscle involved. It is not a peripheral neuromuscular blocker. Anecdotal evidence from case reports suggests that the drug may possess serotonin augmenting effects, which may be clinically relevant in some instances. Animal data indicate that inhibition of serotonergic descending systems in the spinal cord (e.g., 5-HT2 receptors) appears to be a significant component of the action of cyclobenzaprine as a muscle relaxant. Treatment with the drug reduces pain and tenderness and improves mobility. Unlike dantrolene, cyclobenzaprine is not effective for muscle spasm secondary to cerebral or spinal cord disease.

Cyclobenzaprine

Cyclobenzaprine is structurally related to tricyclic antidepressants (e.g., amitriptyline). The potential for cross-sensitivity between tricyclic antidepressants and cyclobenzaprine has not been established; however, caution should be used when changing from one of these chemically-related agents to another. Alternative therapy to cyclobenzaprine should be considered in patients with tricyclic antidepressant hypersensitivity, particularly if the reaction was severe or life-threatening.
Because of a potential risk of cardiac events, the manufacturer contraindicates the use of cyclobenzaprine in patients with hyperthyroidism.
Because of it’s chemical similarity to tricyclic antidepressants (TCAs), use cyclobenzaprine with caution in patients being treated for psychological or psychotic illnesses (e.g., depression or schizophrenia). Cyclobenzaprine is not an effective treatment for depression, and it is unclear if cyclobenzaprine, like the TCAs, can transform depression into mania or hypomania in predisposed individuals (e.g., some patients with bipolar disorder). Cyclobenzaprine is contraindicated for use within 14 days of MAOI therapy. Concomitant use of these drugs has resulted in hyperpyretic crisis seizures and death. Cases of serotonin syndrome have developed when cyclobenzaprine was combined with other serotonergic drugs, such as MAOIs, TCAs, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tramadol, bupropion, meperidine, and verapamil. If concurrent use of these drugs are required, carefully monitor the patient for signs and symptoms of serotonin syndrome. If such a reaction occurs, immediately discontinue cyclobenzaprine and any other serotonergic drug.
Use cyclobenzaprine with caution in patients with a seizure disorder. Tricyclic drugs can lower the seizure threshold. If seizures occur during therapy with cyclobenzaprine, discontinue the drug.

Cyclobenzaprine can induce significant sedation, particularly during the initiation of treatment. Caution patients about driving or operating machinery or performing other hazardous tasks until it is reasonably certain that cyclobenzaprine will not adversely affect their ability to engage in such activities. Advise patients that cyclobenzaprine effects may be additive to impairment from ethanol ingestion. Coadministration with other CNS depressants may also result in additive sedation and impairment.
Cyclobenzaprine, like the tricyclic antidepressants, should not be given to patients who are in the acute recovery phase following acute myocardial infarction; this could cause re-infarction or sudden death. Do not administer cyclobenzaprine to patients with QT prolongation or familial histories of long QT syndrome or in those patients with cardiac conduction defects (e.g., cardiac arrhythmias, AV block, bundle-branch block, or congestive heart failure). Further, use cyclobenzaprine with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction, or may also be at increased risk for QT prolongation. Although the risk of cardiovascular adverse events is higher after acute overdose, patients with cardiovascular disease should be closely monitored. Many adverse cardiovascular effects are associated with the use of tricyclic-related drugs.

Cyclobenzaprine exhibits anticholinergic activity, which may cause gastrointestinal, urinary, ocular, and other side effects. This drug should not be used in patients with paralytic ileus. Patients with increased intraocular pressure, closed-angle glaucoma, prostatic hypertrophy, or urinary retention should receive cyclobenzaprine with caution. The anticholinergic effects of cyclobenzaprine may make the eyes dry, which may cause discomfort for wearers of contact lenses. The use of lubricating drops may be necessary.

Like other tricyclic drugs, cyclobenzaprine may rarely cause liver dysfunction. Cyclobenzaprine should be used with caution in patients with hepatic disease. Cyclobenzaprine is extensive metabolized by the liver to glucuronides. Peak plasma concentrations and AUC of cyclobenzaprine are nearly doubled in patients with hepatic impairment (15 of 16 patients studied had mild hepatic impairment). Cyclobenzaprine is not recommended for patients with moderate to severe hepatic impairment due to insufficient data. In patients with mild hepatic impairment, initiate therapy with 5 mg doses and titrate cautiously; less frequent dosing may be needed.

Cyclobenzaprine has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease, or in children with cerebral palsy. Safety and efficacy of immediate-release cyclobenzaprine in neonates, infants, children, and adolescents under the age of 15 years have not been established, while use of extended-release cyclobenzaprine has not been established in any pediatric patients.
Case reports of cyclobenzaprine use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, decreased body weight and survival were reported among the offspring of pregnant rats who were given oral cyclobenzaprine at doses of 10 and 20 mg/kg/day (equivalent to 3 and 6 times the maximum recommended human dose on a mg/m2 basis) throughout pregnancy and lactation.

There are no data on the presence of cyclobenzaprine in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for cyclobenzaprine and any potential adverse effects on the breast-fed infant from cyclobenzaprine or the underlying maternal condition.

Cyclobenzaprine lowers the seizure threshold. Because of a potential increased risk of seizures, cyclobenzaprine should not be used during intrathecal radiographic contrast administration. Cyclobenzaprine therapy should be discontinued 48 hours before and not restarted until at least 24 hours after myelography.

Patients may be more prone to sunburn during therapy with cyclobenzaprine. Suitable precautions should be taken prior to sunlight (UV) exposure, such as using sunscreens and protective clothing.

Cyclobenzaprine should be used in geriatric adults only if clearly needed. If needed, initiate cyclobenzaprine therapy with low doses and titrate cautiously and consider less frequent dose intervals. Anticholinergic effects of cyclobenzaprine are the most frequently encountered adverse drug effects and cause the greatest morbidity in the elderly. The anticholinergic effects of cyclobenzaprine may be additive with other anticholinergic medications, particularly in the older adult. Elderly patients are at higher risk for adverse CNS (e.g. hallucinations, confusion) and cardiac events due to cyclobenzaprine, potentially leading to falls or other sequelae. Because of reduced clearance and a 40% or larger increase in cyclobenzaprine exposure, the use of cyclobenzaprine extended-release capsules in the elderly patients is not recommended. The plasma concentrations of cyclobenzaprine are elevated 1.7-fold in older adults relative to younger adults. According to the Beers Criteria, skeletal muscle relaxants including cyclobenzaprine are considered potentially inappropriate medications (PIMs) in geriatric patients; avoid use because most muscle relaxants are poorly tolerated by older adults. Some muscle relaxants can cause anticholinergic effects, sedation and are associated with an increased risk of fractures. Also, there is questionable effectiveness of the dosages tolerated by older adults. Avoid drugs with strong anticholinergic properties, such as cyclobenzaprine, in geriatric patients with the following conditions due to the potential for symptom exacerbation or adverse effects: dementia/cognitive impairment (adverse CNS effects), delirium/high risk of delirium (new-onset or worsening delirium), or lower urinary tract symptoms/benign prostatic hyperplasia in men (urinary retention or hesitancy). The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of medications in residents of long-term care facilities; most muscle relaxants are poorly tolerated by older adults due to anticholinergic side effects, sedation, and/or weakness. Cyclobenzaprine has significant anticholinergic properties. Periodic use (e.g., once every 3 months) for no more than 7 days may be appropriate when other interventions or alternative medications are not effective or indicated. Chronic use in individuals with complications due to selected conditions may be indicated, although close monitoring is warranted. Abrupt discontinuation of some muscle relaxants after chronic use may cause adverse effects.
Abrupt discontinuation of cyclobenzaprine treatment after prolonged administration rarely may produce discontinuation symptoms such as nausea, headache, and malaise. Such symptoms are not indicative of addiction.

Gabapentin

Monitor all patients beginning treatment with antiepileptic drugs (AEDs) or currently receiving gabapentin 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). Gabapentin is known to be substantially excreted by the kidney. Adjust the gabapentin dose in patients with renal impairment or renal failure undergoing dialysis, such as hemodialysis.

Because gabapentin causes somnolence and dizziness, advise patients against driving or operating machinery until they have gained enough experience on gabapentin to assess whether gabapentin impairs their ability to perform such tasks. Driving performance studies conducted with a prodrug of gabapentin (gabapentin enacarbil) indicate that gabapentin may cause significant driving impairment. The patients’ ability to assess their own driving competence, as well as their ability to assess the degree of somnolence caused by gabapentin, can be imperfect. The duration of driving impairment after starting therapy with gabapentin is unknown. Whether the impairment is related to somnolence or other effects of gabapentin is unknown.

When using gabapentin, carefully evaluate patients for a history of substance abuse and monitor for signs and symptoms of gabapentin misuse or abuse (e.g., development of tolerance, self-dose escalation, and drug-seeking behavior). A small number of postmarketing cases report gabapentin misuse and abuse.

Initiate gabapentin at the lowest recommended dose and monitor for symptoms of respiratory depression and sedation in elderly patients, patients with underlying pulmonary disease, such as chronic obstructive pulmonary disease (COPD), and during coadministration with other CNS depressants. Serious, life-threatening, and fatal respiratory depression has been reported with gabapentin. Most cases involved coadministration of another CNS depressant, particularly opioids, in patients with underlying respiratory impairment or advanced age. Respiratory depression, if left untreated, may cause respiratory arrest and death. Management of respiratory depression should include observation, necessary supportive measures, and reduction or withdrawal of CNS depressants, including gabapentin. Taper the dose of gabapentin used for analgesia or seizure control before discontinuation.

Ketamine

Ketamine is contraindicated in patients with a hypersensitivity to ketamine or any excipients.

Obtain baseline and periodic liver function tests, including alkaline phosphatase and gamma-glutamyl transferase, in patients receiving ketamine as part of a treatment plan that utilizes recurrent dosing. Recurrent ketamine use is associated with hepatobiliary dysfunction (most often a cholestasis pattern).

Ketamine is contraindicated in patients for whom a significant elevation of blood pressure would constitute a serious hazard, such as those with uncontrolled hypertension, aneurysm, thyrotoxicosis, or a history of stroke. Monitor patients with increased intracranial pressure in a setting with frequent neurologic assessments. Use ketamine with great caution in any patient with the potential for increased intracranial pressure, including those with head trauma, intracranial mass lesions or abnormalities, intracranial bleeding, and hydrocephalus. Alternative agents may be preferable in patients with known structural barriers to normal cerebrospinal fluid flow. Similarly, use ketamine with caution in patients with increased intraocular pressure (e.g., glaucoma), ocular trauma, or those undergoing ocular surgery. Ketamine can have direct negative inotropic properties and should be titrated cautiously in patients with poor ventricular function. The sympathomimetic effect of ketamine can produce elevations in blood pressure, heart rate, and cardiac output, which are typically mild-to-moderate. Ketamine increases coronary perfusion, enhancing myocardial contraction and increasing myocardial oxygen consumption. Hence, ketamine should also be used with caution in patients with cardiac disease, especially coronary artery disease (e.g., angina). Ketamine raises pulmonary arterial pressures somewhat more than systemic pressures and may exacerbate preexisting pulmonary hypertension or congestive heart failure. Monitor vital signs and cardiac function during ketamine administration. In addition, cardiac monitoring may be prudent in patients with thyroid disease requiring thyroid replacement therapy. Ketamine-induced hypertension and tachycardia can be attenuated with the administration of a benzodiazepine, a barbiturate, or a synthetic opioid.

Advise patients to avoid driving or operating machinery within 24 hours of receiving ketamine due to the residual anesthetic effects and potential for drowsiness.

Ketamine administration requires an experienced clinician trained in the use of general anesthetics, airway maintenance, and assisted ventilation as well as requires a specialized care setting where resuscitation equipment is readily available. Continuously monitor vital signs in patients receiving ketamine.

Emergence reactions (e.g., dream-like states, vivid imagery, hallucinations, delirium), sometimes accompanied by confusion, excitement, and irrational behavior may occur during ketamine recovery. Emergence reactions typically last no more than a few hours; however, adverse psychiatric events have occurred and/or persisted days to weeks after ketamine exposure. Incidence can be reduced by using lower recommended doses of ketamine in conjunction with an intravenous benzodiazepine during anesthesia, as well as minimizing verbal, tactile, and visual patient stimulation during recovery. Emergence reactions appear to be less common with intramuscular administration. Reported risk factors include age older than 10 years, females, rapid intravenous administration, preexisting psychosis (e.g., schizophrenia), or patients who normally dream frequently. The use of alternative agents is recommended for procedural sedation in patients with a history of psychosis. Strong psychological factors appear to influence the severity; avoid ketamine in hallucination-prone individuals. Upsetting reactions are much less common in children 10 to 15 years compared to adults and are rare in children younger than 10 years, presumably because a naive child with few life experiences is less likely to interpret unusual dreams or hallucinations as unpleasant. For older children and adults, advanced planning of a pleasant topic to dream about may decrease the incidence of a distressing reaction.

Ketamine has the potential for substance abuse, psychological dependence, and/or criminal diversion. Illicit use of ketamine for its psychological effects (i.e., similar to PCP) and ‘date rape’ use due to its amnestic effects have been reported. Physical dependence, tolerance, and a withdrawal syndrome may occur with long-term use.

The use of ketamine in patients with porphyria is controversial due to contradictory evidence. Many experts consider ketamine anesthesia safe in porphyria patients; safe use in dormant acute intermittent porphyria and hereditary coproporphyria crisis have been reported. Most animal and cell culture models suggest it is non-inducing at clinical concentrations. However, increases in delta-aminolevulinic acid (ALA), porphobilinogen (PBG), and other porphyrins after ketamine anesthesia have been reported and some experts consider porphyria a relative contraindication to its use.

Avoid ketamine as a sole agent for head and neck anesthesia during procedures of the pharynx, larynx, or bronchial tree, including mechanical stimulation of the pharynx; muscle relaxants may be required. Ketamine does not suppress pharyngeal and laryngeal reflexes. Clinicians using ketamine for procedures involving the pharynx (e.g., endoscopy) should make every effort to avoid vigorous stimulation of the posterior pharynx while still preventing accumulation of secretions or blood in the area. neonates and infants younger than 3 months have a higher incidence of ketamine-induced respiratory complications (e.g., laryngospasm, apnea, coughing spells, aspiration), most likely attributable to differences in airway anatomy and age-associated laryngeal excitability. Because of these age-related differences, avoid ketamine in non-intubated patients younger than 3 months and use with caution in those younger than 1 year. Ketamine use is relatively contraindicated in patients with an unsupported airway who have a history of airway instability, tracheal surgery, tracheal stenosis, tracheomalacia, laryngomalacia, pulmonary disease, or an acute pulmonary infection including upper respiratory infection. Ketamine can increase oral secretions, influencing airway patency and further compromising respiratory function, particularly in unsupported patients. Administration of an anticholinergic prior to or concurrently with ketamine may help limit secretions; however, prophylaxis is not routinely recommended during procedural sedation. Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in pediatric patients younger than 3 years, including in utero exposure during the third trimester, may have negative effects on brain development. Consider the benefits of appropriate anesthesia in a young child against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required during the first 3 years of life. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development.

Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in neonates, infants, and children younger than 3 years, including in utero exposure during the third trimester, may have negative effects on brain development. Consider the benefits of appropriate anesthesia in young children against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required during the first 3 years of life. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development. Animal data has suggested ketamine can induce apoptosis when administered in high doses or for prolonged periods. Neurotoxicity in the developing brain may correlate to learning and behavioral abnormalities later in life. Concern about potential human neurotoxicity has prompted investigation, but current evidence is lacking. Results from a small prospective study conducted in 49 young pediatric patients (3 to 22 months, ASA I) undergoing outpatient laser surgery have suggested that repeated exposure to anesthetic ketamine has the potential to negatively impact neurodevelopment. In the study, Bayley Scales of Infant Development-Second Edition scores, a tool used to predict neurodevelopmental outcomes after surgery, were significantly lower after the third exposure to ketamine (each dose = 8 mg/kg IM) compared to baseline in the group with 3 total exposures. In addition, concentrations of the S100B protein were significantly higher after the last procedure compared to baseline in groups with 1, 2, and 3 exposures; elevation of this protein in blood reliably occurs in clinical scenarios associated with central nervous system (CNS) injury. Although the study designs were much different, these results conflict with those from a study evaluating 24 infant patients treated randomly with either a single dose of ketamine 2 mg/kg IV or placebo prior to cardiopulmonary bypass surgery for ventricular septal defect repair, where no significant differences in markers of CNS injury (including S100B expression and Bayley scores) were noted after ketamine exposure.

In general, dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Ketamine administration is not recommended during pregnancy, labor, or obstetric delivery because safe use has not been established. Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures during the third trimester of pregnancy may have negative effects on fetal brain development. Consider the benefits of appropriate anesthesia in pregnant women against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required prior to delivery. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child and/or mother. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development.

Use ketamine with careful monitoring in breast-feeding mothers; alternate agents are preferred. Minimal data indicate that ketamine use in breast-feeding mothers may not affect the breast-fed infant or lactation.

Cyclobenzaprine

Case reports of cyclobenzaprine use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, decreased body weight and survival were reported among the offspring of pregnant rats who were given oral cyclobenzaprine at doses of 10 and 20 mg/kg/day (equivalent to 3 and 6 times the maximum recommended human dose on a mg/m2 basis) throughout pregnancy and lactation.

Gabapentin

There are no adequate and well-controlled studies of gabapentin in pregnant women.Data from cohort studies describing the neonatal risks of gabapentin treatment during pregnancy are inconclusive. Gabapentin actively crosses the placenta. Among 6 neonates born to mothers who were taking gabapentin (doses ranging from 900 to 3,200 mg/day), umbilical cord-to-maternal plasma concentration ratios ranged from 1.3 to 2.11 (mean, 1.74) at delivery. Gabapentin concentrations in the neonates declined to an average of 27% (range, 12% to 36%) of cord blood concentrations at 24 hours postpartum. One infant was born premature at 33 weeks; however, all deliveries were uneventful and all neonates were born in healthy condition. In a prospective cohort study, rates of major malformations among neonates were similar between 223 pregnancies with gabapentin exposure and 223 unexposed pregnancies (4.1% exposed vs. 2.5% unexposed, p = 0.555). Major malformations included 2 ventricular septal defects, anencephaly, macrocephaly, microretrognathism, cutis marmorata, pyloric stenosis, bilateral varus clubfoot, and cryptorchidism. In all cases of major malformations, women received concomitant treatment with other medications during pregnancy; therefore, a causal relationship to gabapentin cannot be established. No major malformations occurred in neonates born to women exposed to gabapentin monotherapy during pregnancy (n = 36). There were higher rates of preterm births (10.5% vs. 3.9%, p = 0.019), low birth weight (less than 2,500 g) (10.5% vs. 4.4%, p = 0.033), and admission to neonatal intensive care or special care nursery (38% vs. 2.9%, p less than 0.001) among neonates with gabapentin exposure compared to unexposed neonates. Two cases of possible poor neonatal adaptation syndrome occurred in neonates with gabapentin exposure late in pregnancy compared to no cases among unexposed infants; these 2 neonates were also exposed to other psychotropic medications. In a cohort of 39 women who were exposed to gabapentin during their first trimester (97%) and throughout gestation (81.8%), malformations occurred in 3 of 44 live births. Hypospadia was reported in a neonate exposed to gabapentin and valproate; a missing kidney occurred in a neonate exposed to gabapentin and phenobarbital, and a minor malformation of the left external ear canal and 2 small skin tags at the jaw occurred in a neonate exposed to gabapentin and lamotrigine. Since exposure to multiple antiepileptic drugs occurred during these pregnancies, a causal relationship to gabapentin cannot be established. No malformations occurred in 11 patients exposed to gabapentin monotherapy during pregnancy. In animal studies, gabapentin has been fetotoxic during organogenesis at doses of 1 to 4 times the maximum recommended human dose on a mg/m2 basis. Delayed ossification of bones in the skull, limbs, and vertebrae were reported when pregnant mice received oral gabapentin (500, 1,000, or 3,000 mg/kg/day) during organogenesis. The no-effect dose for toxicity (500 mg/kg/day) is less than the maximum human recommended dose (MRHD) of 3,600 mg/kg on a body surface area (mg/m2) basis. Increased incidences of hydroureter and/or hydronephrosis were observed at all doses tested in studies in which rats received oral gabapentin (500 to 2,000 mg/kg/day). An increased incidence of fetal loss was also noted at all doses tested when pregnant rabbits were treated with oral gabapentin (60, 300, or 1,500 mg/kg) during organogenesis. Physicians are advised to recommend that pregnant patients receiving gabapentin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry.

Ketamine

Ketamine administration is not recommended during pregnancy, labor, or obstetric delivery because safe use has not been established. Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures during the third trimester of pregnancy may have negative effects on fetal brain development. Consider the benefits of appropriate anesthesia in pregnant women against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required prior to delivery. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child and/or mother. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development.

Lidocaine

Lidocaine is classified as FDA pregnancy category B. Reproductive studies conducted in rats have not demonstrated lidocaine-induced fetal harm; however, animal studies are not always predictive of human response. There are no adequate or well controlled studies of lidocaine in pregnant women. Local anesthetics are known to cross the placenta rapidly and, when administered for epidural, paracervical, pudendal, or caudal block anesthesia, and to cause fetal toxicity. The frequency and extent of toxicity are dependent on the procedure performed. Maternal hypotension can result from regional anesthesia, and elevating the feet and positioning the patient on her left side may alleviate this effect. Topical ocular application of lidocaine is not expected to result in systemic exposure. When lidocaine is used for dental anesthesia, no fetal harm has been observed; lidocaine is generally the dental anesthetic of choice during pregnancy and guidelines suggest the second trimester is the best time for dental procedures if they are necessary. A study by the American Dental Association provides some evidence that, when needed, the use of dental local or topical anesthetics at 13 weeks to 21 weeks of pregnancy or later is likely safe and does not raise incidences of adverse pregnancy outcomes or other adverse events; the study analyzed data from the Obstetrics and Periodontal Therapy (OPT) trial, a multicenter study of over 800 pregnant patients in the early to mid second trimester who received required dental procedures.

Cyclobenzaprine

There are no data on the presence of cyclobenzaprine in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for cyclobenzaprine and any potential adverse effects on the breast-fed infant from cyclobenzaprine or the underlying maternal condition.

Gabapentin

Gabapentin is excreted in human breastmilk. A breast-feeding infant could be exposed to a maximum gabapentin dose of approximately 1 mg/kg/day. The effects of gabapentin on the breast-fed infant and milk production are unknown.Because of the potential for adverse reactions in breast-feeding infants, discontinue breast-feeding or gabapentin enacarbil, taking into account the importance of the drug to the mother. For other gabapentin products, consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for gabapentin and any potential adverse effects on the breast-fed infant from gabapentin or the underlying maternal condition. Only use gabapentin in breast-feeding women if the benefits clearly outweigh the risks.The infant dose of gabapentin excreted in breast milk was examined in 4 infants, 3 of which were 2 to 3 weeks of age and 1 who was approximately 3 months old. The average daily maternal dosage of gabapentin was 1,575 mg (range, 600 to 2,100 mg/day). A single milk sample was obtained approximately 10 to 15 hours after the last dose. Assuming a breast milk consumption of 150 mL/kg/day, the relative infant dose of gabapentin was estimated to be 0.2 to 1.3 mg/kg/day, which approximates 1.3% to 3.8% of the weight-adjusted maternal dose. At 2 to 3 weeks after delivery, 2 infants had detectable gabapentin plasma concentrations that were under the normal range of quantification, and 1 had an undetectable concentration. At 3 months, the gabapentin plasma concentration in another infant was under the normal range of quantification. No adverse effects were reported.

Ketamine

Use ketamine with careful monitoring in breast-feeding mothers; alternate agents are preferred. Minimal data indicate that ketamine use in breast-feeding mothers may not affect the breast-fed infant or lactation.

Lidocaine

According to the manufacturers, caution should be exercised when lidocaine is administered to breastfeeding women (regardless of dosage formulation). Lidocaine is excreted in breast milk with a milk:plasma ratio of 0.4. Many specific dosage forms, including Lidoderm brand lidocaine transdermal patches, have not been studied in breastfeeding women. The American Academy of Pediatrics lists lidocaine as usually compatible with breast-feeding. When lidocaine is used for dental or short-term, limited local anesthesia, the healthy term infant can generally safely nurse as soon as the mother is awake and alert. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternal drug exposure, healthcare providers are encouraged to report the adverse effect to the FDA.

Cyclobenzaprine

Adverse reactions most commonly reported with cyclobenzaprine use, resulting from CNS depression and/or anticholinergic response, are drowsiness (16—39%), fatigue (6%), headache (5%), and dizziness (3—11%). Reactions that were reported in between 1% and 3% of patients taking cyclobenzaprine tablets include irritability, decreased mental acuity, asthenia, blurred vision, headache, nervousness, and confusion. Among 36 patients who received cyclobenzaprine 30 mg extended-release capsules in a pharmacokinetic study, 100% had somnolence, 17% had headache, 19% had dizziness, 6% had tremor, 6% had disturbance in attention, and 3% had blurred vision. Among 126 patients who also received cyclobenzaprine 30 mg extended-release capsules, 6% had dizziness, 3% had fatigue, and 2% had somnolence. Among 127 recipients of a 15 mg dose, 3% had dizziness, 3% had fatigue, and 1% had somnolence. The following adverse reactions were noted postmarketing or during clinical trials at an incidence of < 1%: malaise, seizures, ataxia, vertigo, dysarthria, tinnitus, tremors, hypertonia, convulsions, muscle twitching, disorientation, insomnia, depressed mood, abnormal sensations, anxiety, agitation, psychosis, abnormal thinking and dreaming, hallucinations, excitability, paresthesias, and diplopia. Adverse events for which a causal relationship is unclear and an incidence is unknown include increased libido, decreased libido, abnormal gait, delusions, aggressive behavior, paranoia, peripheral neuropathy, Bell’s palsy, alteration in EEG patterns, and extrapyramidal symptoms. Elderly patients are at higher risk for adverse CNS (e.g. hallucinations, confusion), potentially leading to falls or other sequelae.
Anaphylaxis (e.g., anaphylactic shock, anaphylactoid reactions), angioedema, pruritus, facial edema, urticaria, and rash (unspecified) have occurred postmarketing or with an incidence < 1% in patients who received cyclobenzaprine 10 mg three times daily in clinical trials. Adverse events for which a causal relationship is unknown include dyspnea.
The following adverse reactions of cyclobenzaprine were noted postmarketing or during clinical trials at an incidence of < 1%: increased urinary frequency and/or urinary retention. Adverse events for which a causal relationship is unclear and the incidence is unknown include inappropriate ADH syndrome (SIADH), impaired urination, dilatation of urinary tract, impotence (erectile dysfunction), libido increase, libido decrease, testicular swelling, gynecomastia, breast enlargement, and galactorrhea.
Cyclobenzaprine is closely related to the tricyclic antidepressants, and tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, and prolongation of the conduction time leading to myocardial infarction and stroke. Cyclobenzaprine is contraindicated for use during the acute recovery phase of myocardial infarction and in patients with arrhythmias, heart block conduction disturbances, or congestive heart failure. Among 36 patients who received cyclobenzaprine extended-release capsules, 6% had palpitations. Sinus tachycardia, arrhythmia, peripheral vasodilation, palpitations, and hypotension were noted postmarketing or during clinical trials with 10 mg three times daily at an incidence of < 1%. Adverse events for which a causal relationship is unclear and the incidence is unknown include hypertension, myocardial infarction, heart block, chest pain (unspecified), edema, syncope, and stroke. Elderly patients are at higher risk for adverse cardiac events, potentially leading to falls or other sequelae. A case report of torsades de pointes with concurrent droperidol and cyclobenzaprine exists.

Xerostomia is a common adverse effect of cyclobenzaprine; 7—32% of patients who took the 5 or 10 mg tablet during clinical trials or during a postmarketing survelliance program had the event. Among 36 patients who received cyclobenzaprine 30 mg extended-release capsules, 58% had xerostomia, 8% had nausea, 6% had dysgeusia, and 8% had dry throat. Among 126 patients who also received cyclobenzaprine 30 mg extended-release capsules, 14% had xerostomia, 3% had nausea, 4% had dyspepsia, and 3% had constipation. Among 127 recipients of a 15 mg dose, 6% had xerostomia, 3% had nausea, and 1% had constipation. Adverse reactions noted in 1—3% of patients with the tablet were nausea, constipation, dyspepsia, and unpleasant taste. The following adverse reactions were noted postmarketing or during clinical trials with 10 mg three times daily at an incidence of < 1%: ageusia, vomiting, anorexia, diarrhea, abdominal pain, gastritis, thirst, flatulence, tongue edema, abnormal liver function, hepatitis, jaundice, and cholestasis. Adverse events for which a causal relationship is unclear and an incidence is unknown include paralytic ileus, tongue discoloration, stomatitis, parotid swelling, hyperglycemia, hypoglycemia, weight gain, and weight loss.
Among 36 patients who received cyclobenzaprine 30 mg extended-release capsules, 6% had acne vulgaris. Diaphoresis was noted postmarketing or during clinical trials with 10 mg three times daily at an incidence of < 1%. Adverse events for which a causal relationship is unknown include photosensitivity and alopecia.

Local weakness was noted postmarketing or during clinical trials with cyclobenzaprine 10 mg three times daily at an incidence of < 1%. Adverse events for which a causal relationship is unknown include myalgia.

Adverse events for which a causal relationship to cyclobenzaprine is unclear and the incidence is unknown include purpura, bone marrow depression, leukopenia, eosinophilia, and thrombocytopenia.
Cases of serotonin syndrome have been reported when cyclobenzaprine is used in combination with the following drugs: selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, tramadol, bupropion, meperidine, verapamil, and MAO inhibitors. Serotonin syndrome is a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome. Symptoms may include mental status changes (agitation, confusion, hallucinations), autonomic instability (changes in blood pressure, diaphoresis, hyperthermia, tachycardia), neuromuscular abnormalities (ataxia, clonus, hyperreflexia, muscle rigidity, tremor), and/or gastrointestinal symptoms (nausea, vomiting, diarrhea). If serotonin syndrome becomes evident during treatment, cyclobenzaprine and any other serotonergic agents should be discontinued and appropriate medical treatment should be initiated.

Ketamine

Ketamine-induced hypertension and sinus tachycardia are dose-dependent and mediated through the sympathetic nervous system with the release of endogenous catecholamines. Elevation of blood pressure begins shortly after ketamine injection, reaches maximum levels within a few minutes, and usually returns to preanesthetic levels within 15 minutes of injection. In the majority of cases, the systolic and diastolic blood pressure peaks from 10% to 50% above baseline shortly after induction, but the elevation can be higher and longer in some patients. Ketamine-induced hypertension and tachycardia can be attenuated with the administration of a benzodiazepine, a barbiturate, or a synthetic opioid. In general, ketamine’s indirect sympathomimetic effects compensate for its direct negative inotropic properties; however, hypotension, bradycardia, and even cardiac arrest may occur in patients with diminished myocardial contractility. Arrhythmia (arrhythmia exacerbation) has also been reported in patients receiving ketamine.

Respiratory depression and apnea are rare with ketamine use and more likely to occur after rapid administration of high doses, when central nervous system injuries or abnormalities are present, or in neonates. Administer intravenous doses over at least 60 seconds. Most patients do not require assisted ventilation with ketamine anesthesia; however, laryngospasm and other forms of airway obstruction have occurred and may require airway intervention. In addition, ketamine can increase bronchial secretions, influencing airway patency and compromising respiratory function, particularly in unsupported patients. Administration of an anticholinergic prior to or concurrently with ketamine may help limit secretions.

Hypersalivation is a well-known effect of ketamine mediated via cholinergic stimulation. Ketamine stimulates both salivary and tracheobronchial secretions which may influence airway patency and compromise respiratory function, particularly in unsupported patients. To lessen such problems, administration of an anticholinergic prior to or concurrently with ketamine is recommended in most clinical situations. Anorexia, nausea, and vomiting have also been observed with ketamine use. Prophylactic ondansetron may slightly reduce the rate of vomiting (number needed to benefit: 9 or more). Emesis appears to be more frequent late in the recovery phase. Emesis was reported in 3.8% (6/156 patients; 1 while sedated and 5 well into recovery) and 6.7% (69/1,022 patients; 8 while sedated and 60 during recovery) of pediatric patients receiving intravenous and intramuscular ketamine, respectively, for procedural sedation in the emergency department with no evidence of aspiration. Drug-induced emesis was responsible for the onset of laryngospasm in 1 patient. Because protective airway reflexes are maintained during ketamine anesthesia, the risk of clinical aspiration when ketamine is used as a sole agent is minimal. However, protective reflexes may be diminished by supplementary anesthetics and muscle relaxants. Therefore, it is prudent to administer ketamine on an empty stomach to forgo the risk of aspiration. Ketamine may be administered in patients without an empty stomach when, in the judgment of the practitioner, the benefits of the drug outweigh the risks. Ketamine-induced nausea and vomiting are not usually severe and most patients are able to take liquids by mouth shortly after regaining consciousness.

Increased intracranial pressure has been reported after the administration of ketamine. Monitor patients with elevated intracranial pressure closely with frequent neurological assessments.

Diplopia, nystagmus, and increased intraocular pressure (ocular hypertension) have been noted with ketamine administration. Dissociative anesthesia results in a state of catalepsy in which the eyes may remain open with slow nystagmus and intact corneal reflexes. This “disconnected” stare may be disconcerting to caregivers who are present before full anesthesia recovery; hence, education and proper preparation are recommended prior to anesthesia. Limiting verbal, tactile, and visual stimulation in patients who appear awake but are still recovering may reduce the incidence of emergence reactions.

Emergence reactions are common during ketamine recovery, occurring in approximately 12% of adult patients. Psychological manifestations may vary in severity, presenting as pleasant dream-like states, vivid imagery, nightmares, hallucinations, or emergence delirium. In some cases, these states are accompanied by confusion, excitability, and irrational behaviors which may be recalled as unpleasant. Emergence reactions typically last no more than a few hours; however, adverse psychiatric events have occurred and/or persisted days to weeks after ketamine exposure. Upsetting reactions are much less common in children 10 to 15 years compared to adults and are rare in children younger than 10 years, presumably because a naive child with few life experiences is less likely to interpret unusual dreams or hallucinations as unpleasant. For older children or adults, advanced planning of a pleasant topic to dream about may decrease the incidence of a distressing reaction. Incidence can be reduced by using lower recommended doses of ketamine in conjunction with an intravenous benzodiazepine during anesthesia, as well as minimizing verbal, tactile, and visual patient stimulation during recovery. Severe reactions may require a small hypnotic dose of a short- or ultra short-acting benzodiazepine or barbiturate.

Physiological dependence and tolerance are possible with prolonged administration of ketamine. Psychological dependence has been reported with illicit use. Symptoms of illicit ketamine use include anxiety, dysphoria, disorientation, insomnia, flashbacks, hallucinations, and psychosis. Users of ketamine describe sensations of floating to being separated from their bodies. A withdrawal syndrome associated with daily intake of large doses may present as craving, fatigue, poor appetite, and anxiety. Ketamine causes amnesia and abrupt loss of consciousness and is odorless and tasteless, which allows it to be added beverages without being detected. These properties have led it to be used as a “date rape” drug.

Involuntary movements of the head and extremities, often described as tonic-clonic, are frequent with ketamine use; these movements are unrelated to painful stimuli and are not indicative of the need for additional anesthetic. Movements are usually not intense enough to interfere with the performance of the procedure. Brief and sometimes intense myoclonia and twitching may be confused with seizure activity; however, these movements are benign and not associated with EEG changes. Skeletal muscle hypertonia and rigidity may also occur with ketamine use. Severe hypertonia is more frequent at high doses. A report describes generalized extensor spasm with opisthotonus in 2 infants receiving high doses of ketamine (total dose: 14 to 19 mg/kg within approximately 1 hour); in both cases, muscular hyperactivity ceased approximately 5 minutes after the administration of a small dose of pentobarbital.

Anaphylaxis/anaphylactoid reactions, transient erythema, maculopapular rash, and an injection site reaction including localized pain and rash have been reported with ketamine use.

There have been case reports of genitourinary pain in patients with a history of chronic ketamine use for off-label indications. Lower urinary tract and bladder symptoms including dysuria, increased urinary frequency, urinary urgency, urinary incontinence, and hematuria have been reported in individuals with a history of chronic ketamine use or abuse. Cystitis (including noninfective, interstitial, ulcerative, erosive, and hemorrhagic cystitis), hydronephrosis, and reduced bladder capacity have been reported upon diagnostic assessment. Consider ketamine cessation if genitourinary pain continues in the setting of other genitourinary symptoms.

Transient central diabetes insipidus (DI) has been associated with continuously infused ketamine in 2 case reports. A 2-year-old female with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) and stable hypertrophic cardiomyopathy was admitted to the hospital for pneumonia. She subsequently developed respiratory failure requiring mechanical ventilation. At 10 hours after initiation of a continuous ketamine infusion, the patient developed polyuria (urine output 8 mL/kg/hour), hypernatremia, elevated serum osmolality, and decreased urine osmolality. A vasopressin infusion was started, and the patient responded appropriately. Medications administered before ketamine infusion included continuous infusions of lorazepam, fentanyl, and dexmedetomidine, as well as vancomycin and cefotaxime for the pneumonia; only the antibiotics were continued after ketamine initiation. The Naranjo adverse drug reaction probability scale indicated a probable relationship (score 7) between the development of DI and ketamine. The other case describes transient DI in a 28-year-old male who received ketamine for pain management after spinal cord injury. Similar to the pediatric case, the patient experienced DI within hours after receiving ketamine, and responded well to desmopressin. The exact mechanism of ketamine-induced DI is unclear; it may involve ketamine’s N-methyl-D-aspartate receptor antagonism and inhibition of glutamate-stimulated arginine vasopressin release from the neurohypophysis.

Recurrent ketamine use is associated with hepatobiliary dysfunction (most often a cholestasis pattern). Obtain baseline and periodic liver function tests, including alkaline phosphatase and gamma-glutamyl transferase, in patients receiving ketamine as part of a treatment plan that utilizes recurrent dosing.

Lidocaine

Lidocaine crosses the blood brain barrier and can produce significant central nervous system (CNS) toxicity, particularly when high plasma concentrations (more than 6 mcg/mL free base) are achieved. CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness (dizziness), anxiety (i.e., nervousness or apprehension), restlessness, euphoria, confusion, drowsiness, tinnitus, blurred vision or double vision, vomiting, metallic taste, dysgeusia, sensations of heat (hot flashes), cold or numbness, hyperesthesia, hypoesthesia, asthenia, twitching, tremor, convulsions (seizures), unconsciousness, respiratory depression, and respiratory arrest. Agitation, dysarthria, oral hypoesthesia, and disorientation have also been reported with systemic use. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness after the administration of lidocaine is usually an early sign of a high blood concentration of the drug and may occur as a consequence of rapid absorption. In some patients, the symptoms of CNS toxicity are minor and transient. Dizziness and vomiting occurred in 0.9% and 1% of patients, respectively, who were treated with the lidocaine intradermal injection system during clinical trials.

During caudal or lumbar epidural block, unintentional penetration of the subarachnoid space may occur. Adverse effects depend upon the amount of drug given subdurally and may include spinal block of varying magnitude, low blood pressure secondary to spinal block, fecal incontinence and urinary incontinence, and loss of perineal sensation and sexual function. In a prospective review of 10,440 patients who received lidocaine HCl for spinal anesthesia, positional headaches, low blood pressure and backache were reported in 3% of patients, shivering was reported in 2%, and peripheral nerve symptoms, nausea, respiratory inadequacy and double vision were reported in < 1% of patients. Many of these observations may be related to local anesthetic techniques, with or without a contribution from the local anesthetic. Neurologic effects seen following spinal anesthesia include paresthesias, weakness and paralysis of lower extremities, low blood pressure, high or total spinal block, urinary retention, headache, back pain, septic meningitis, meningismus, arachnoiditis, shivering, cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. Persistent motor, sensory, and/or autonomic (sphincter control) deficit of lower spinal segments with slow (several months) or incomplete recovery has been reported rarely. Following spinal administration with lidocaine 5% with Dextrose, transient neuropathic pain, developing in the buttocks and radiating to the lateral thighs and calves may be seen. Complete resolution of symptoms usually takes place within 3 days but may persist for up to 2 months. Nausea occurred in 2% of patients who were treated with the lidocaine intradermal injection system during clinical trials.

Cardiac effects of local anesthetics such as lidocaine are due to the interference of conduction within the myocardium. Cardiac effects are seen at very high systemic doses and usually occur after the onset of CNS toxicity. Lidocaine-induced adverse cardiovascular effects include myocardial depression, sinus bradycardia, hypotension, cardiovascular collapse, and cardiac arrest. These effects typically occur with high plasma drug concentrations but have occurred with smaller doses in rare instances. Cardiovascular and CNS side effects resulting from lidocaine administration should be treated with general supportive physiologic measures such as oxygen therapy, assisted ventilation, and IV fluids. Monitor blood pressure and the electrocardiogram during intravenous lidocaine administration. If cardiovascular side effects such as hypotension, arrhythmia exacerbation, or excessive depression of cardiac conduction occur (e.g., prolonged PR interval or widened QRS complex), discontinue lidocaine administration and re-evaluate treatment options. Combining lidocaine with a vasoconstrictor increases the likelihood of producing anxiety, palpitations, dizziness, headache, restlessness, tremor, angina, and hypertension.

Local anesthetics generally are known to cross the placenta. For obstetric use, fetal heart rate should be monitored continuously because fetal bradycardia has occurred with high plasma levels of lidocaine. Maternal hypotension can result from regional anesthesia. Patient position can alleviate this problem, and the injection should be performed with the patient in the left lateral decubitus position to displace the gravid uterus, thereby minimizing aortocaval compression. Because of the profound motor blockade produced when used epidurally, lidocaine can cause decreased uterine contractility and further decrease maternal expulsive efforts. Unintended fetal intracranial injection of local anesthetics has occurred from attempted pudendal or paracervical block. Failure to achieve adequate anesthesia with standard doses should arouse suspicion of intracranial or intravascular injections. Infants so affected often present with unexplained neonatal depression at birth and can develop seizures within 6 hours as a result of high serum concentrations. Fetal bradycardia and fetal acidosis have resulted from paracervical injections.

Systemic adverse reactions after appropriate application of topical or transdermal lidocaine are unlikely because of the small amount of lidocaine absorbed. The skin at the site of treatment may develop erythema, swelling, or dysesthesia (abnormal sensation). Application site reactions may occur during or immediately after treatment with the lidocaine transdermal patch. Blisters, ecchymosis, depigmentation (skin discoloration), skin erosion, exfoliation, flushing, skin irritation (including burning sensation and dermatitis), papules, petechiae, pruritus, or vesicles may develop on the skin at the site of application. These reactions are usually mild and transient resolving within a few minutes to hours. Preexisting inflammation or infection increases the risk of developing serious skin side effects. There have been reported cases of permanent injury to extraocular muscles requiring surgical repair following retrobulbar administration of lidocaine. Additionally, small doses of local anesthetics injected into the head and neck area may produce an adverse reaction similar to systemic toxicity after unintentional intravascular injection. During adult and pediatric clinical trials of lidocaine injectable powder (Zingo), erythema (an injection site reaction) occurred in 53% to 67.3% of patients who received active drug, petechiae in 44% to 46.4% of patients, edema in 4.3% to 8% of patients, and pruritus in 1% to 9.4% of patients. Burning and venipuncture site hemorrhage occurred in 0.54% and 0.4% of adults, respectively. A total of 4% of pediatric patients experienced application site reactions that included ecchymosis, burning, pain, contusion, and hemorrhage.

Allergic and anaphylactoid reactions have been infrequently associated with lidocaine administration. Allergic reactions may manifest as cutaneous lesions, urticaria, edema, angioedema, bronchospasm, dermatitis, dyspnea, laryngospasm, pruritus, or anaphylactic shock. Allergic reactions may occur as a result of sensitivity either to local anesthetic agents or to other components in the formulation. The detection of sensitivity by skin testing is of questionable value. There have been no reports of cross-sensitivity between lidocaine and para-amino-benzoic acid derivatives (procaine, tetracaine, benzocaine, etc.).

Methemoglobinemia has been reported with local anesthetic use. Signs and symptoms of methemoglobinemia may occur immediately or may be delayed some hours after local anesthetic exposure and are characterized by cyanotic skin discoloration and abnormal coloration of the blood. Other symptoms may include headache, rapid heart rate, shortness of breath, dizziness, and drowsiness. Since methemoglobin concentrations may continue to rise, immediately discontinue lidocaine to avoid serious central nervous system and cardiovascular adverse events including seizures, coma, arrhythmias, and death. Depending on the severity of symptoms, patients may require supportive care, such as oxygen therapy and hydration. More severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

Local anesthetics such as lidocaine administered by a continuous infusion to a joint space may cause chondrolysis (necrosis and destruction of cartilage). The FDA has received 35 reports of chondrolysis in patients given continuous intra-articular infusions of local anesthetics with elastomeric infusion devices to control post-surgical pain. Data suggest that the reported cases of chondrolysis are not associated with any single manufacturer of elastomeric infusion devices. In all but 1 patient, chondrolysis occurred after shoulder surgeries. The local anesthetics +/- epinephrine were infused for 48 to 72 hours directly into the intra-articular space using an elastomeric pump. The most commonly reported site of infusion was the glenohumeral (glenoid) space (46%), and bupivacaine was at least 1 of the local anesthetics used in all 35 cases. Joint pain, stiffness, and loss of motion were reported as early as the second month after infusion receipt. Chondrolysis was diagnosed a median of 8.5 months after the infusion. In more than half of these reports, the patients required additional surgery including arthroscopy or arthroplasty. In addition to the 35 bupivicaine-related cases, the FDA has received four additional reports of chondrolysis in patients administered continuous intra-articular infusions of lidocaine in the shoulder. It is not known which specific factor or combination of factors contributed to the development of chondrolysis. The infused local anesthetic drugs, the device materials, and/or other sources may have resulted in the development of chondrolysis. In vitro data do suggest that bupivacaine, lidocaine, and ropivacaine cause chondrolysis. Local anesthetics are not indicated for continuous intra-articular postoperative infusions or for use with infusion devices such as elastomeric pumps. Health care professionals are advised to NOT use elastomeric infusion devices for continuous intra-articular infusion of local anesthetics after orthopedic surgery. The FDA is requiring the drug manufacturers to update their product labels to warn healthcare professionals about the reported cases of chondrolysis after continuous intra-articular infusion with local anesthetics. The FDA is also requiring the manufacturers of pumps that may be used to infuse local anesthetics such as elastomeric infusion devices to have similar warnings for their products. Of importance, single intra-articular injections of local anesthetics in orthopedic procedures have been used for many years without any reported occurrence of chondrolysis. If a patient has received a continuous intra-articular postoperative infusion of a local anesthetic, monitor the patient for the emergence of the signs and symptoms of chondrolysis such as joint pain, stiffness, and loss of motion. Also, instruct the patient to report any such symptoms. The appearance of these symptoms can be variable and may begin two or more months after surgery.

Systemic adverse reactions after appropriate application of lidocaine ophthalmic gel are unlikely because of the small amount of lidocaine absorbed. After instillation of lidocaine ophthalmic gel, the most common reported side effects included conjunctival hyperemia, corneal epithelial changes, headache, and ocular irritation (burning upon instillation). Lidocaine ophthalmic gel, when used over a prolonged period, may cause permanent corneal opacification and ulceration leading to visual impairment.

Drugs used to administer anesthesia have been associated with malignant hyperthermia. Although it is unknown whether local anesthetics, such as lidocaine, trigger this reaction, it is recommended that a standard protocol for management be available when lidocaine is administered in hospital environments. Early unexplained symptoms such as tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful management includes prompt discontinuation of suspected triggering agents and institution of treatment.

Store this medication 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.

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