vSoothe 1 Vaginal Cream

 

Overview of vSoothe 1 Vaginal Cream

Dosage Strength of vSoothe 1 Vaginal Cream

Amitriptyline HCl / Baclofen / Gabapentin 2/2/2% 30 mL Topi-Click PERL Dispenser

General Information

Amitriptyline HCL / Baclofen / Gabapentin Cream is a topical or intravaginal therapy used to treat symptoms related to vulvodynia and Provoked Vestibulodynia. These conditions cause vulvar discomfort, usually burning pain, and dyspareunia, in the absence of any specific cause.1 Vestibulodynia can have a profound effect on women’s sexuality and psychological well-being.2

Amitriptyline

Amitriptyline is a tertiary amine tricyclic antidepressant (TCA) that is metabolized to an active metabolite, nortriptyline. Tertiary amines are generally more sedating and have greater anticholinergic effects than secondary amines. Amitriptyline is also related to the skeletal muscle relaxant cyclobenzaprine, although amitriptyline is not believed to possess muscle-relaxant properties. Amitriptyline is FDA-approved for the treatment of adults with major depressive disorder (MDD). Clinically, amitriptyline is also used to treat neuropathic pain and other conditions.

Baclofen

Baclofen is an oral skeletal muscle relaxant. It is a structural analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Clinically, baclofen is used to treat spasticity and improve mobility in patients with multiple sclerosis and other spinal cord lesions by decreasing the number and severity of spasms and relieving associated pain, clonus, and muscle rigidity.

Gabapentin

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.3

Topical gabapentin in the treatment of localized and generalized vulvodynia4

Participants: 150 patients presenting with entry dyspareunia
Administration: Topical (local)
Dosage: 2% Cream
Conclusion: 80% of respondents demonstrated at least a 50% improvement in pain scores. Topical gabapentin seems to be well-tolerated and associated with significant pain relief in women with vulvodynia.

Use of amitriptyline cream in the management of entry dyspareunia due to provoked vestibulodynia5

Participants: 35 women
Administration: Topical (local)
Dosage: 2% Cream
Conclusion: Topical amitriptyline cream should be considered for first-line treatment in the management of patients with provoked vestibulodynia causing entry dyspareunia. The response rate is reasonable (56%), and it eliminates the problems with systemic administration, namely, drowsiness and the difficulty patients have in accepting antidepressant medication for their condition.

Topical Amitriptyline-Baclofen Cream for the Treatment of Provoked Vestibulodynia2

Participants: 38 women
Administration: Topical (local)
Dosage: 2% Baclofen & 2% Amitriptyline Cream
Conclusion: 71% response rate in women with refractory symptoms and the overall tolerability of treatment.

Pharmacokinetics

Transdermal application results in localized action as well as peripheral nerve and capillary uptake. As such, the expected pharmacokinetics for each of compounds mimics those of the individual compounds when administered topically. The differences resulting from simultaneous application have not been studied.

Interactions

Amitriptyline Hydrochloride / Baclofen / Gabapentin Vaginal Cream acts synergistically via three distinct pharmacologically active compounds and each has its own list of compounds it interacts with. Interactions resulting from the combination of these compounds have not been studied and may include more than the sum of all compounds. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Contraindications/Precautions

Amitriptyline

Amitriptyline is contraindicated in patients with a hypersensitivity to amitriptyline or any of its inactive ingredients.6 Patients with a hypersensitivity to amitriptyline may experience a tricyclic antidepressant hypersensitivity reaction to other tricyclics. In some case reports, cross-allergenicity did not occur in patients who experienced a rash from the primary tricyclic and were switched to an alternate tricyclic.7 However, because the data are too limited to be conclusive, it is generally advisable to substitute with an antidepressant from another class in patients with a known hypersensitivity to amitriptyline. When considering use of an alternate tricyclic, it is prudent to avoid other cyclic compounds if the patient has experienced a severe or life-threatening reaction to the primary agent. Cross-sensitivity is possible in patients with a carbamazepine hypersensitivity. The manufacturer of carbamazepine contraindicates use in patients with a hypersensitivity to tricyclic compounds.8 The potential for cross-reactivity between tricyclics and other structurally similar compounds such as cyclobenzaprine or tetracyclic antidepressants (e.g., maprotiline, amoxapine) has not been established.

Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) simultaneously; use with MAOI therapy is contraindicated. When it is desired to replace MAOI therapy with amitriptyline, a minimum of 14 days should be allowed to elapse after the MAOI is discontinued. Amitriptyline should then be initiated cautiously with a gradual increase in dosage until optimum response is achieved.6

Amitriptyline is contraindicated in patients who are in the acute recovery phase following acute myocardial infarction; use of amitriptyline could cause sudden death.6 Amitriptyline may cause orthostatic hypotension, particularly in the initial dosing titration. Use tricyclic antidepressants (TCAs) with caution and with close monitoring in patients with any cardiac disease (e.g., heart failure, history of myocardial infarction, congenital heart disease). TCAs, including amitriptyline, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia, and prolongation of the conduction time. Myocardial infarction and stroke have been reported with drugs of this class. Although the risk of cardiovascular adverse events is higher after acute overdose, patients with cardiovascular disease should be closely monitored via ECGs and clinical exams. TCAs should not be given to patients with QT prolongation. Use amitriptyline with caution in patients with conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, 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.9 Females, elderly patients, patients with diabetes, thyroid impairment, malnutrition, a history of alcohol abuse, or hepatic impairment may also be at increased risk for QT prolongation.101112131415 Rarely, TCAs are used in pediatric patients for the treatment of attention-deficit hyperactivity disorder (ADHD). There have been reports of sudden death in pediatric patients treated with TCAs that were not associated with overdoses. Although cardiac monitoring is recommended, it is unclear whether monitoring can prevent a sudden death event. The American Heart Association recommends conducting a detailed patient and family history and physical examination prior to initiating ADHD pharmacologic treatment, and obtaining a baseline ECG is a reasonable addition to the initial evaluation. Once the medication is started, a repeat ECG may be helpful if the original ECG was obtained before the child was 12 years old, if cardiac symptoms develop, or there is a change in family history. If a child or adolescent has any significant findings on physical examination, ECG, or family history, a pediatric cardiologist should be consulted before the medication is initiated.16

Amitriptyline should be used with caution in children with a known family history of heart disease or who are taking medications that cause QT prolongation. QTc interval prolongation, tachycardias, and other side effects have been reported in children who have taken tricyclic antidepressants (TCAs); there are rare reports of deaths due to cardiovascular side effects. Routine cardiovascular monitoring has been suggested for children receiving TCAs due to the potential of these agents to produce adverse cardiac effects.6171819

All effective antidepressants can transform depression into mania or hypomania in predisposed individuals. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. If a patient develops manic symptoms, amitriptyline should be withheld and appropriate therapy initiated to treat the manic symptoms. Additionally, depression may be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Also use TCAs with caution in patients with psychotic disorders (e.g., schizophrenia). Psychotic symptoms may be precipitated in some individuals. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of unusual changes in behavior or suicidality. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. It should be noted that amitriptyline is not approved for use in treating bipolar depression.6

Amitriptyline can induce significant sedation, particularly during the initiation of treatment. Amitriptyline may enhance the response to alcohol, the effects of barbiturates, and increase sedation or central nervous system (CNS) effects during coadministration with other CNS depressants. Patients should use caution with ethanol ingestion. In patients who may use alcohol excessively (e.g., alcoholism), the potentiation of CNS effects may increase the danger inherent in any suicide attempt or overdosage. Patients should use caution when driving or operating machinery until they are aware of the effects of the medication.6

Amitriptyline should be used with extreme caution in patients with a preexisting seizure disorder because tricyclic antidepressants (TCAs) can lower the seizure threshold. If seizures occur during TCA therapy, the TCA should be discontinued. Concurrent administration of amitriptyline and electroconvulsive therapy (ECT) may increase the hazards associated with such therapy. Such treatment should be limited to patients for whom it is essential.6

Tricyclic antidepressants (TCAs), such as amitriptyline, should be used with caution in patients with hepatic disease. Metabolism of tricyclic antidepressants may be altered in patients with hepatic impairment. Rarely, TCAs have caused hepatitis and jaundice, which are reversible on discontinuation. Liver function tests (LFTs) should be performed if symptoms occur and the drug discontinued if there is persistent elevation of enzymes.6

Amitriptyline should be discontinued several days before elective surgery because of the risk of adverse reactions during surgery, including increased sensitivity to catecholamines and potential cardiovascular reactions.6

The anticholinergic effects of tricyclic antidepressants (TCAs) limit the use of the drugs in certain patients. The anticholinergic effects of amitriptyline may be significant and are additive with other anticholinergic medications. These actions can decrease GI motility, causing constipation and in some cases, paralytic ileus. Patients who have risk factors for urinary retention, such as those with benign prostatic hypertrophy, should also be treated with caution. Anticholinergic effects appear most frequently and cause the greatest morbidity in elderly patients.6

Caution is recommended when prescribing amitriptyline to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.6

The anticholinergic effects of amitriptyline may increase lens discomfort for wearers of contact lenses. Mydriasis, disturbance of accommodation, and dry eyes may contribute to blurred vision and lens intolerance. The use of lubricating drops may be necessary.

Patients who develop a continued fever and a sore throat during therapy with a tricyclic antidepressant (TCA) should have leukocyte and differential blood counts performed. The TCA should be discontinued if there is evidence of pathological neutrophil depression. On rare occasions, there have been reports of leukopenia, agranulocytosis, neutropenia, thrombocytopenia, anemia, and pancytopenia in association with TCA use.6

Tricyclic antidepressants (TCAs) like amitriptyline should be used with caution in patients who have thyroid disease. Close supervision is required when amitriptyline is given to patients with hyperthyroidism or those patients with hypothyroidism who are receiving thyroid medication.6

Tricyclic antidepressants (TCAs) affect blood glucose concentrations because of their effect on the endocrine system; both elevation and lowering of blood sugar levels have been reported. Therefore, amitriptyline should be used with caution in patients with diabetes mellitus.6 TCAs should also be used with caution in patients with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma) in whom these drugs may provoke hypertensive crises.20

Tricyclic antidepressants lower the seizure threshold. Because of a potential increased risk of seizures, amitriptyline should not be used during intrathecal radiographic contrast administration. Tricyclic antidepressant therapy should be discontinued 48 hours before and not restarted for at least 24 hours after myelography.21

Patients may be more prone to sunburn during therapy with amitriptyline. Patients should avoid excessive exposure to sunlight since there have been reports of photosensitization during the use of tricyclic antidepressants (TCAs). Suitable precautions should be taken to limit effects prior to sunlight (UV) exposure, such as wearing long-sleeved clothing and a hat, and using sunscreens.22

Following prolonged therapy, abrupt discontinuation of a tricyclic antidepressant (TCA) should be avoided because it could precipitate a drug discontinuation syndrome. Symptoms of cholinergic rebound such as nausea, vomiting, or diarrhea may occur. Other typical symptoms of antidepressant discontinuation syndrome include flu-like symptoms, insomnia, imbalance, sensory disturbances, and hyperarousal.23

Amitriptyline dose selection should generally be cautious in the geriatric patient. Initiation at the low end of the dosage range with slow titration and careful observation is recommended. Geriatric patients are particularly sensitive to the peripheral and central anticholinergic side effects of amitriptyline and may be at increased risk for falls.6 According to the Beers Criteria, tricyclic antidepressants (TCAs) are considered potentially inappropriate medications (PIMs) in geriatric patients; avoid TCA use due to the potential for orthostatic hypotension, anticholinergic effects or toxicity (e.g., constipation, urinary difficulties, blurred vision, dry mouth, delirium), or sedation. Avoid TCA use in geriatric patients with the following conditions due to the potential for symptom exacerbation or adverse effects: syncope (increased risk of orthostatic hypotension or bradycardia), dementia/cognitive impairment (drug-induced 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). Further, the Beers expert panel recommends avoiding TCAs in elderly patients with a history of falls or fractures, unless safer alternatives are not available, since TCAs can produce ataxia, impaired psychomotor function, syncope, and additional falls. If amitriptyline must be used in an elderly 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. Lastly, TCAs can cause or exacerbate hyponatremia and SIADH and the elderly are at increased risk of developing these conditions. Sodium levels should be closely monitored when starting or changing dosages of TCAs in older adults.24 The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities; the duration of therapy should be in accordance with pertinent literature and clinical practice guidelines. TCAs are rarely the medications of choice in the elderly because of strong anticholinergic and sedating properties. However, TCAs may be appropriate in residents being treated for neurogenic pain when the benefits outweigh the risks and safer medications or interventions are either not indicated or have been considered, attempted, and failed. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and/or suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, somnolence, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk for falls. Prior to discontinuation, many antidepressants may need a taper to avoid a withdrawal syndrome. Monitoring should consist of a review for continued need at least quarterly, and documentation of the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated.24

Tobacco smoking has been shown to increase the clearance of tricyclic antidepressants (TCAs), including amitriptyline, by inducing hepatic microsomal enzymes. The effect of tobacco on hepatic microsomal enzymes is not related to the nicotine component, so sudden smoking cessation may result in a reduced clearance of amitriptyline and increased amitriptyline effects, despite the initiation of nicotine replacement products.

Baclofen

Geriatric patients or patients with cerebral lesions as opposed to spinal lesions may experience increased toxicity to baclofen. Elderly patients require lower initial doses and slow dose titration. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of medications in residents of long-term care facilities. According to the OBRA guidelines, most muscle relaxants are poorly tolerated by older adults due to anticholinergic side effects, sedation, and/or weakness. However, 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 multiple sclerosis, spinal cord injuries, cerebral palsy, and other select conditions may be indicated, although close monitoring is warranted. Abrupt discontinuation of some muscle relaxants may cause or predispose individuals to seizures or hallucinations.24

Patients with pre-existing psychiatric disorders (e.g., bipolar disorder, depression, psychosis, schizophrenia) are at increased risk for baclofen-induced psychiatric adverse reactions.

Hyperglycemia is associated with oral and intrathecal baclofen use.2526Use with appropriate caution in patients with diabetes mellitus.

Baclofen has caused deterioration in the control of seizures and EEG changes in patients with epilepsy. Baclofen should be prescribed cautiously to patients with a history of a seizure disorder or a history of seizures.

Cases of baclofen toxicity (manifesting as encephalopathy, abdominal pain, and in some cases, seizures and respiratory depression) have been reported in patients with severe renal impairment (e.g., serum creatinine more than 2 mg/dL) and renal failure who received oral baclofen.27Most patients who became toxic received low oral doses of baclofen (e.g., 15 to 30 mg/day) for a short duration. Baclofen toxicity can occur with relatively low doses within 24 to 48 hours of initiation of oral therapy. In renal failure patients receiving dialysis, doses not exceeding 5 mg/day orally have been suggested; although toxicity may still occur. Therefore, in patients with severe renal impairment or renal failure, alternative therapies should be considered. If a patient develops baclofen toxicity, hemodialysis may be a useful treatment to alleviate clinical symptoms.27Similar toxicity is not expected with intrathecal use of baclofen as resultant drug plasma concentrations are 100-fold lower then those experienced with oral use.28

Patients should be warned that baclofen may impair the ability to perform certain tasks that require mental alertness or physical coordination such as driving or operating machinery. Patients should also be cautioned that the central nervous system (CNS) depressant effects of baclofen may be additive to those of ethanol ingestion and coadministration with other CNS depressants.

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.293031

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.29

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.32

Pregnancy

Amitriptyline

There are no adequate and well-controlled studies of amitriptyline use in pregnant women; therefore, amitriptyline should only be used in pregnancy if the benefits to the mother outweigh the possible risks to the fetus. Adverse events, including CNS effects, limb deformities, and developmental delays have been reported in infants of mothers taking amitriptyline during pregnancy. Some studies in animals have shown teratogenic effects at amitriptyline doses ranging from 9 to 33 times the maximum recommended human dose (MRHD); however, other studies in animals at doses up to 13 times the MRHD have not shown teratogenicity. Tricyclic antidepressants (TCAs) cross the placenta. Neonatal complications after in utero exposure to TCAs including withdrawal symptoms, hypoglycemia, respiratory diagnoses, developmental delays, and jaundice have been reported. Withdrawal symptoms in neonates have included lethargy, cyanosis, tachypnea with respiratory acidosis, jitteriness, tremors, hypertonia, hypotonia, feeding difficulties, and seizures. Neonates exhibiting signs or symptoms of drug toxicity or withdrawal should be carefully monitored. The impact of in utero exposure to antidepressants or antipsychotics compared to no psychotropic exposure was assessed in infants 6 months of age using the Infant Neurological International Battery (INFANIB), a neuromotor exam that tests posture, tone, reflexes, and motor skills, and using a visual habituation paradigm of a neutral female face. The infants exposed to antipsychotics (n = 22) showed significantly lower INFANIB scores than those exposed to an antidepressant (n = 202) or no psychotropic drug (n = 85). There were no significant differences regarding habituation between the medication exposure groups. In a prospective trial evaluating the effects of in utero exposure to tricyclic or tetracyclic antidepressants in pediatric patients 15 to 71 months of age compared to similar non-exposed controls, exposure to antidepressants did not adversely affect IQ, language, behavior, or temperament. The effects of amitriptyline during labor and obstetric delivery are unknown. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at http://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/antidepressants.63334353637

Baclofen

There are no adequate and well controlled studies of baclofen use during human pregnancy. Based on animal data, baclofen may cause fetal harm. Baclofen should only be used during pregnancy when the potential benefit to the mother outweighs the potential risk to the fetus.38 28 2639 During administration of baclofen to animals during organogenesis at doses exceeding the maximum recommended human dose (MRHD), there were increased incidences of omphaloceles (ventral hernias), incomplete sternebral ossification, and/or unossified phalangeal nuclei of forelimbs and hindlimbs. A reduction in mean fetal weight with consequent delays in skeletal ossification was also observed.2639 Human data are limited. In 3 cases, healthy infants were delivered by C-section after in utero exposure to intrathecal baclofen infusions (doses of 140 to 1,400 mcg/day). Follow up in 2 of the cases revealed normal development at 12 months and 24 months of age, respectively.4041 A neonatal abstinence syndrome may occur shortly after birth in neonates following intrauterine baclofen exposure. In 1 case report, a woman received 80 mg of oral baclofen daily during pregnancy and post-partum. In order to prevent NAS, the neonate was placed on oral baclofen at initial dosage of 0.1 mg/kg/day for 4 days, followed by a daily decrease of 0.01 mg/kg/day until the drug was discontinued after 13 days. Of note, the neonate received approximately one-third of the total daily dose of baclofen from breast milk. Daily assessments for NAS were done using the modified Finnegan scoring system. Additional pharmacological intervention was not needed, and the neonate was discharged 3 days after the taper ended.42 [61274] The effects of baclofen in labor and obstetric delivery are unknown.26

Gabapentin

There are no adequate and well-controlled studies of gabapentin in pregnant women.29Data 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.43 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.44 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.45 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.29

Breast-feeding

Amitriptyline

Because tricyclic antidepressants (TCAs), including amitriptyline, are excreted into breast milk, the benefits and risks of breast-feeding should be carefully weighed if TCA therapy is needed in the mother. According to the manufacturer, because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug.33 The effects of TCAs on the nursing infant are not known but may be of concern, particularly with prolonged exposure.46A pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum and, therefore, may be the preferred antidepressants in breast-feeding mothers.47

Baclofen

At therapeutic oral doses, baclofen is excreted in human milk; caution is recommended when using the drug during breast-feeding.39 38 However, it is not known if baclofen is detectable in breast milk after intrathecal administration; the labeling for intrathecal products recommends that a decision be made whether to discontinue breast-feeding or to discontinue intrathecal baclofen injection, considering the importance of intrathecal baclofen therapy to the mother.28 26Limited information indicates that oral baclofen to the lactating mother appears in low levels in milk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. Monitor newborn infants for signs of sedation. Low intrathecal doses and topical application are unlikely to affect the nursing infant.42 In a woman who received a single 20 mg oral dose of baclofen 14 days postpartum, the highest serum concentration of the drug occurred at 3 hours and the highest milk level was obtained at 4 hours. The total amount of drug recovered from the milk during the 26-hour sampling period was about 0.1% of the maternally ingested dose.48 If baclofen treatment is continued, monitor the nursing infant for sedation.42

Gabapentin

Gabapentin is excreted in human breast milk. 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.2930Because 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.31 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.2930The 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.49

Adverse Reactions/Side Effects

Amitriptyline Hydrochloride / Baclofen / Gabapentin Vaginal Cream may relieve symptoms associated with vulvodynia and Provoked Vestibuladynia.

This cream is formulated to act locally so side effects are generally minimal, but may include skin irritation, headache, dizziness, and somnolence. However, possible side effects include but are not limited to those of each of the cream’s components. The side effects of these compounds in combination have not been studied.

Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, swollen painful area on the leg.

Storage

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.

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