Bremelanotide/Oxytocin/Tadalafil Troche

Overview of Bremelanotide / Oxytocin / Tadalafil Troches

Dosage Strength of Bremelanotide / Oxytocin / Tadalafil Troches

Bremelanotide / Oxytocin / Tadalafil Troches:
1 mg/100 IU/10 mg (10 Troches/Pack)
1 mg/100 IU/20 mg (10 Troches/Pack)
2 mg/100 IU/20 mg (10 Troches/Pack)

General Information

Bremelanotide

Bremelanotide is an injectable melanocortin receptor agonist. It is administered subcutaneously and indicated in premenopausal females for the treatment of Hypoactive Sexual Desire Disorder (HSDD), or low sexual desire. It has a unique mechanism of action that helps activate brain pathways that are involved in normal sexual responses. Safety and efficacy were established in premenopausal females 19 to 56 years of age with HSDD that causes marked distress or interpersonal difficulty and is NOT due to a co-existing medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug substance. Bremelanotide is not indicated for the treatment of HSDD in postmenopausal women, males, or to enhance sexual performance. In clinical trials, about 25% of patients treated with bremelanotide had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2 to 6, with higher scores indicating greater sexual desire) compared to approximately 17% of those who took placebo. Bremelanotide is used "as needed" prior to anticipated sexual activity; women do not have to use the drug on a daily basis.1

Oxytocin

Endogenous oxytocin is a hormone secreted by the supraoptic and paraventricular nuclei of the hypothalamus and stored in the posterior pituitary. It stimulates contraction of uterine smooth muscle during gestation and causes milk ejection after milk has been produced in the breast. Oxytocin has been associated with mating, parental, and social behaviors. Oxytocin is released during intercourse in both men and women, which has led to the belief that it is involved in sexual bonding. There is speculation that in addition to facilitating lactation and the birthing process, the hormone facilitates the emotional bond between mother and child.2 Oxytocin has also been studied in autism and have some sort of relation to the social and developmental impairments associated with the disease.3 Clinically, oxytocin is used most often to induce and strengthen labor and control postpartum bleeding. Intranasal preparations of oxytocin, used to stimulate postpartum milk ejection, are no longer manufactured in the U.S. Oxytocin was approved by the FDA in 1962.

Tadalafil

Tadalafil is a selective phosphodiesterase (PDE) type 5 inhibitor similar to sildenafil and vardenafil. It is administered orally for the treatment of male erectile dysfunction (ED), pulmonary arterial hypertension (PAH), benign prostatic hypertrophy (BPH), or the concurrent treatment of erectile dysfunction and BPH. Tadalafil does not inhibit prostaglandins as do some agents for treating impotence (e.g., alprostadil). Unlike sildenafil, visual disturbances have not been reported with tadalafil, which is more selective for PDE5 than for PDE6 present in the retina. The duration of action of tadalafil for the treatment of ED (up to 36 hours) appears to be longer than that of sildenafil and vardenafil. Because PDE inhibitors promote erection only in the presence of sexual stimulation, the longer duration of action of tadalafil allows for more spontaneity in sexual activity. According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy.4 Tadalafil was in phase II trials for the treatment of female sexual dysfunction, however, further investigation was discontinued. FDA approval was granted November 2003 for treatment of male erectile dysfunction (ED), and in January 2008, approval was granted for once daily use without regard to timing of sexual activity. Tadalafil (Adcirca) was FDA approved for the treatment of pulmonary arterial hypertension (PAH) in May 2009. In clinical studies of patients with pulmonary arterial hypertension (PAH), tadalafil-treated patients experienced improved exercise capacity and less clinical worsening compared to placebo. In October 2011, tadalafil received FDA approval for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) and for the concurrent treatment of erectile dysfunction and BPH.

Mechanism of Action

Bremelanotide

Bremelanotide is a melanocortin receptor (MCR) agonist that nonselectively activates several receptor subtypes with the following order of potency: MC1R, MC4R, MC3R, MC5R, MC2R. At therapeutic dose levels, binding to MC1R and MC4R is most relevant. Neurons expressing MC4R are present in many areas of the central nervous system (CNS). The mechanism by which bremelanotide improves HSDD in women is unknown. The drug's unique mechanism of action is assumed to activate selected brain pathways that are involved in normal sexual responses. The MC1R is expressed on melanocytes; binding at this receptor leads to melanin expression and increased skin pigmentation.1

Oxytocin

Synthetic oxytocin elicits the same pharmacological response produced by endogenous oxytocin, with cervical dilation, parity, and gestational age as predictors of the dose response to oxytocin administration for labor stimulation.5 Oxytocin increases the sodium permeability of uterine myofibrils, indirectly stimulating contraction of the uterine smooth muscle. The uterus responds to oxytocin more readily in the presence of high estrogen concentrations and with the increased duration of pregnancy. There is a gradual increase in uterine response to oxytocin for 20 to 30 weeks gestation, followed by a plateau from 34 weeks of gestation until term, when sensitivity increases.5 Women who are in labor have a greater response to oxytocin compared to women who are not in labor; only very large doses will elicit contractions in early pregnancy. In the term uterus, contractions produced by exogenous oxytocin are similar to those that would occur during spontaneous labor. Oxytocin increases the amplitude and frequency of uterine contractions, which transiently impede uterine blood flow and decrease cervical activity, causing dilation and effacement of the cervix.

Oxytocin causes contraction of the myoepithelial cells surrounding the alveolar ducts of the of the breast. This forces milk from the alveolar channels into the larger sinuses, and thus facilitates milk ejection. While oxytocin possesses no galactopoietic properties, if it is absent the milk-ejection reflex in the breast fails.

Oxytocin causes dilation of vascular smooth muscle, thus increasing renal, coronary, and cerebral blood flow. Blood pressure usually remains unaffected, but with the administration of very large doses or high concentration solutions blood pressure may decrease transiently. This transient decrease in blood pressure leads to reflex tachycardia and an increase in cardiac output; any fall in blood pressure is usually followed by a small, but sustained, increase in blood pressure.

Oxytocin does possess antidiuretic effects, but they are minimal. If oxytocin is administered with an excessive volume of electrolyte-free IV solution and/or at too rapid a rate, the antidiuretic effects are more apparent and water intoxication can result.

Tadalafil

Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum. Tadalafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Tadalafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. In vitro studies show that tadalafil is selective for PDE5 and is 10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is 10,000 fold more potent for PDE5 than for PDE3 found in the heart and blood vessels. Also, tadalafil has 700-fold greater selectivity for PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. Compare this selectivity to the selectivity of sildenafil which has only a 10-fold selectivity for PDE5 versus PDE6. This lower selectivity of sildenafil for PDE5 vs PDE6 is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of sildenafil. Further, tadalafil is 9000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4. PDE11 is an enzyme found in human skeletal muscle, prostate, testes, and in other tissues. Inhibition of human recombinant PDE11A1, and to a lesser extent, PDE11A4 activities occur at tadalafil concentrations within the therapeutic range. The physiological role and clinical effects of PDE11 inhibition in humans have not been elucidated.

The mechanism by which tadalafil reduces the symptoms of benign prostatic hyperplasia (BPH) has not been established; however, the effect of PDE5 inhibition on cGMP concentrations in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, bladder, and their vascular supply.6

Tadalafil can inhibit PDE5 present in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in relaxation of pulmonary vascular smooth muscle and subsequent pulmonary vasodilation, thereby making tadalafil an effective agent in treating pulmonary hypertension.7

Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Dyspepsia is one of the most common adverse reactions associated with PDE5 inhibitor therapy.

Contraindications/Precautions

Bremelanotide

Bremelanotide is not indicated for the treatment of hypoactive sexual desire disorder (HSDD) in men or in postmenopausal women. Bremelanotide is not indicated to enhance sexual performance.1

Bremelanotide is contraindicated in patients who have uncontrolled hypertension or known cardiac disease. Bremelanotide is not recommended for patients at high risk for cardiac disease. Before initiating bremelanotide, and periodically during treatment, consider the patient's cardiovascular risk and ensure blood pressure is well-controlled. Bremelanotide transiently increases blood pressure and reduces heart rate after each dose. In clinical studies, bremelanotide induced maximal increases of 6 mmHg in systolic blood pressure (SBP) and 3 mmHg in diastolic blood pressure (DBP) that peaked between 2 to 4 hours post-dose. There was a corresponding reduction in heart rate up to 5 beats per minute. Blood pressure and heart rate returned to baseline usually within 12 hours postdose. No additive effects were seen for blood pressure or heart rate following repeat daily dosing (given 24 hours apart) for up to 16 days. To minimize the risk of more pronounced blood pressure effects, advise patients to not take more than 1 bremelanotide dose within 24 hours. Administering more than 8 doses/month is not recommended. Few patients in the phase 3 program received more than 8 doses/month. More frequent dosing increases the length of time per month when blood pressure is increased.1

Bremelanotide can cause nausea/vomiting. Nausea is the most commonly reported adverse reaction, reported in 40% of bremelanotide-treated patients, requiring anti-emetic therapy in 13% of bremelanotide-treated patients and leading to premature discontinuation from the trials for 8% of bremelanotide-treated patients. Vomiting is among the most common adverse reactions with bremelanotide, occurring in 4.8% of patients. Nausea improves for most patients with the second dose. Consider discontinuing bremelanotide for persistent or severe nausea or initiating anti-emetic therapy for those patients who are bothered by nausea but wish to continue with bremelanotide treatment. In one study, premedication with ondansetron before bremelanotide dosing had no significant effect vs. placebo in preventing treatment-induced nausea.1

Bremelanotide may cause focal skin hyperpigmentation due to the melatonin agonist activities of the drug. There is a higher risk of skin discoloration in patients with darker skin and with daily dosing of bremelanotide. Focal hyperpigmentation occurred on the face, gingiva, and breast in 1% of female patients in clincial trials receiving the drug in accordance with recommended dosing. Resolution did not occur in all patients who experienced skin hyperpigmentation, despite drug discontinuation. Patients should not use more than 8 doses of the drug per month. Consider discontinuing the drug if skin hyperpigmentation develops.1

Use bremelanotide with caution in patients with severe hepatic disease (Child-Pugh C; score 10 to 15) or severe renal impairment (eGFR less than 30 mL/minute/1.73 m2), including patients with renal failure, because these patients may have an increase in the incidence and severity of adverse reactions (e.g., nausea and vomiting) due to increased drug exposure. Bremelanotide has not been evaluated in patients with severe hepatic impairment. No dosage adjustment is needed in patients with mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2) or mild to moderate hepatic impairment (Child-Pugh A or B, score 5 to 9).1

The use of bremelanotide during pregnancy is not recommended. Contraception requirements are advised; females of child-bearing potential should be counseled regarding appropriate methods of contraception while on therapy. Bremelanotide should be discontinued if pregnancy is suspected. Pregnant women exposed to bremelanotide and healthcare providers are encouraged to call the Bremelanotide Pregnancy Exposure Registry at (877) 411-2510. Based on findings in animal studies, the use of bremelanotide in pregnant women may be associated with the potential for fetal harm. In animal reproduction and development studies, daily subcutaneous administration of bremelanotide to pregnant dogs during the period of organogenesis at exposures greater than or equal to 16 times the maximum recommended dose (based on area under the concentration-time curve or AUC) produced fetal harm. In mice subcutaneously dosed with bremelanotide during pregnancy and lactation, developmental effects were observed in the offspring at greater than or equal to 125-times the maximum recommended dose (based on AUC). However, the lowest bremelanotide dose associated with fetal harm has not been identified for either species.1

There is no information on the presence of bremelanotide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated maternal condition.1
Safety and efficacy of bremelanotide have not been established in postmenopausal females (age 57 years and older) or geriatric female patients. The drug is not indicated for use in these patient populations.1

The safety and effectiveness of bremelanotide have not been established in pediatric patients (infants, children, or adolescents).1

Oxytocin

Oxytocin is indicated during pregnancy to induce labor; it precipitates uterine contractions and abortion.5

Endogenous oxytocin is involved in the process of lactation and therefore, oxytocin has been used in mothers having difficulty with engorgement and breast-feeding. Because several small studies have failed to show a beneficial effect, oxytocin is not used for this indication. Oxytocin is excreted in the breast-milk, but is not expected to have adverse effects in the infant.8

Parenteral oxytocin should be used only by qualified professional personnel in a setting where intensive care and surgical facilities are immediately available. Furthermore, according to the manufacturer, oxytocin should only be used when induction of labor is necessary for medical reasons. It should not be used for elective induction of labor as available data are insufficient to evaluate the risk-benefit ratio in this indication. During oxytocin administration, uterine contractions, fetal and maternal heart rate, maternal blood pressure, and, if possible, intrauterine pressure should be continuously monitored to avoid complications. If uterine hyperactivity occurs, oxytocin administration should be immediately discontinued; oxytocin-induced stimulation of the uterine contractions usually decreases soon after discontinuance of the drug. The induction or continuance of labor with oxytocin should be avoided when the following conditions or situations are present: evidence of fetal distress, fetal prematurity, abnormal fetal position (including unengaged head), placenta previa, uterine prolapse, vasa previa, cephalopelvic disproportion, cervical cancer, grand multiparity, previous surgery of the uterus or cervix (including 2 or more cesarean deliveries), active genital herpes infection, or in any condition presenting as an obstetric emergency requiring surgical intervention. Use of oxytocin in any of these settings can aggravate the condition or cause unnecessary fetal or maternal distress.

Oxytocin may possess antidiuretic effects, and prolonged use can increase the possibility of an antidiuretic effect. Prolonged use of oxytocin and administration in large volumes of low-sodium infusion fluids are not recommended, particularly in patients with eclampsia or who have unresponsive uterine atony. Antidiuretic effects have the potential to lead to water intoxication and convulsive episodes due to hypertension.

Tadalafil

Your health care provider needs to know if you have any of these conditions: bleeding disorders; eye or vision problems, including retinitis pigmentosa; Peyronie’s disease, or history of priapism (painful and prolonged erection); heart disease, angina, a history of heart attack, irregular heart beats; high or low blood pressure; history of blood diseases; history of stomach bleeding; kidney disease; liver disease; stroke; an unusual or allergic reaction to tadalafil. If you notice any changes in your vision while taking this drug, call your doctor or health care professional as soon as possible. Stop using this medicine and call your healthcare provider right away if you have a loss of sight in one or both eyes. Contact your healthcare provider right away if the erection lasts longer than 4 hours or if it becomes painful. If you experience symptoms of nausea, dizziness, chest pain or arm pain upon initiation of sexual activity after taking this medicine, you should refrain from further activity and call your healthcare provider immediately. Do not drink alcohol when taking this medicine as alcohol can increase your chances of getting a headache or getting dizzy, increasing your heart rate or lowering your blood pressure. Using this medicine does not protect you or your partner against HIV infection or other sexually transmitted infections.

Tadalafil is contraindicated in patients with a known hypersensitivity to the drug or any component of the tablet.7 6

The safety and efficacy of combinations of tadalafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.6

Because the efficacy of concurrent use of tadalafil and alpha-blockers in the treatment of benign prostatic hyperplasia (BPH) has not been adequately studied, and due to the potential vasodilatory effects of such combination treatment, tadalafil is not recommended for use with alpha-blockers when treating BPH (see Drug Interactions).6

Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Consistent with its known effects on the nitric oxide/cGMP pathway, tadalafil may potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive tadalafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once tadalafil has been administered.

Use tadalafil cautiously in patients with renal impairment. Dosing recommendations vary depending upon the severity of renal impairment, indication, and the dosing regimen being used (see Dosage in renal impairment). Tadalafil is not recommended in patients receiving the drug on a once daily basis for erectile dysfunction, benign prostatic hyperplasia, or pulmonary arterial hypertension when the creatinine clearance is less than 30 ml/min or the patient has renal failure or is receiving dialysis.6

Use tadalafil with caution in patients with altered hepatic function secondary to hepatic disease and/or drug-induced inhibition. Dosage modifications are needed in patients with mild to moderate hepatic impairment (see Dosage). In patients with severe hepatic impairment, use of tadalafil is not recommended because of insufficient data. Additionally, tadalafil is metabolized by CYP3A4 in the liver. Dosage adjustments are necessary in patients taking potent CYP3A4 inhibitors such as ritonavir, ketoconazole, and itraconazole (see Dosage and Drug Interactions).

There is a degree of cardiac risk associated with sexual activity; therefore, prescribers should evaluate the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction. Tadalafil and other PDE5 inhibitors have mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. The following groups of patients with cardiac disease were excluded from clinical safety and efficacy trials for tadalafil, and, therefore, the manufacturer does not recommend the use of tadalafil in these groups until more data are available: myocardial infarction within the last 90 days; coronary artery disease resulting in unstable angina or angina occurring during sexual intercourse; NYHA Class II or greater heart failure in the last 6 months; uncontrolled cardiac arrhythmias; hypotension (< 90/50 mmHg); uncontrolled hypertension ( 170/100 mmHg); or a stroke within the last 6 months. Based on recommendations for sildenafil by the American College of Cardiology, it is recommended that tadalafil be used with caution in the following: patients with active coronary ischemia (angina) who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status (hypovolemia); patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of tadalafil. Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Also, patients with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) or severely impaired autonomic control of blood pressure can be sensitive to the action of vasodilators, including PDE5 inhibitors. Due to the pulmonary vasodilation caused by tadalafil, patients with pulmonary veno-occlusive disease (PVOD) may experience significant worsening in cardiovascular status. Due to a lack of clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. The possibility of associated PVOD should be considered should signs of pulmonary edema occur when tadalafil is administered.

Prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been associated with PDE5 inhibitor administration. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Use tadalafil, and other agents for the treatment of erectile dysfunction, with caution in patients with penile structural abnormality (such as angulation, cavernosal fibrosis, or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell disease, leukemia, multiple myeloma, polycythemia, or history of priapism).6 9

Educate patients that tadalafil, when used for erectile dysfunction, offers no protection against sexually transmitted disease. Counsel patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, as appropriate to the individual circumstances.

Use tadalafil cautiously in patients with pre-existing visual disturbance. Post-marketing reports of sudden vision loss have occurred with phosphodiesterase inhibitors. Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve. Although visual disturbances have been reported rarely with tadalafil, there is no safety information on the administration of tadalafil to patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa. A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. Therefore, it is recommended that tadalafil not be administered to these patients until further data are available.

Geriatric patients ( = 65 years) made up approximately 25% of patients in the primary efficacy and safety studies of tadalafil for the treatment of erectile dysfunction and 28% of patients in the clinical study of tadalafil for pulmonary arterial hypertension. In clinical trials for benign prostatic hyperplasia, geriatric patients greater than 65 years of age accounted for 40% of study participants and those 75 years of age and older accounted for 10% of study participants. No overall differences in efficacy and safety were observed between older and younger patients for these indications. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered.6 7

Prior to initiating treatment with tadalafil for benign prostatic hyperplasia (BPH), consideration should be given to other urological conditions that may cause similar symptoms. Prostate cancer and benign prostatic hyperplasia (BPH) cause many of the same symptoms and frequently they coexist. Prior to starting tadalafil therapy for BPH, patients should be evaluated to rule out the presence of prostate cancer.6

Tadalafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies of tadalafil in pregnant women. According to the manufacturer, Adcirca should be used during pregnancy only if clearly needed;7 Tadalafil is not indicated for use in women.6

Use tadalafil cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Like sildenafil, tadalafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.10 Additionally, tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), which is found in platelets. Some data indicate that tadalafil does not potentiate the increase in bleeding time caused by aspirin. However, the manufacturer recommends caution when administering tadalafil to patients with significant active peptic ulcer disease (PUD) since the effects of the drug in this patient population have not been formally studied.6

It is not known if tadalafil is excreted in breast milk. Adcirca should be used with caution in breast-feeding women;7 Tadalafil is not indicated for use in women.6 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 maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), which is found in platelets. Some data indicate that tadalafil does not potentiate the increase in bleeding time caused by aspirin. However, the manufacturer recommends caution when administering tadalafil to patients with significant hematological disease (e.g., bleeding disorders) since the effects of the drug in this patient population have not been formally studied.6

This list may not include all possible contraindications.

Pregnancy

Bremelanotide

Oxytocin

Oxytocin is indicated during pregnancy to induce labor; it precipitates uterine contractions and abortion.5

Tadalafil

Breastfeeding

Bremelanotide

Oxytocin

Endogenous oxytocin is involved in the process of lactation and therefore, oxytocin has been used in mothers having difficulty with engorgement and breast-feeding. Because several small studies have failed to show a beneficial effect, oxytocin is not used for this indication. Oxytocin is excreted in the breastmilk, but is not expected to have adverse effects in the infant.8

Tadalafil

It is not known if tadalafil is excreted in breast milk. Adcirca should be used with caution in breast-feeding women;7 Tadalafil is not indicated for use in women.6 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated coAnchorndition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Adverse Reactions/Side Effects

Bremelanotide

Bremelanotide transiently increases blood pressure and reduces heart rate after each dose; bremelanotide is contraindicated in patients with uncontrolled hypertension. Before initiating bremelanotide, and periodically during treatment, consider the patient's cardiovascular risk and ensure blood pressure is well-controlled. To minimize the risk of more pronounced blood pressure effects, advise patients to not take more than one bremelanotide dose within 24 hours. In clinical studies, bremelanotide induced maximal increases of 6 mmHg in systolic blood pressure (SBP) and 3 mmHg in diastolic blood pressure (DBP) that peaked between 2 to 4 hours post dose. There was a corresponding reduction in heart rate up to 5 beats per minute. Blood pressure and heart rate returned to baseline usually within 12 hours postdose. No additive effects were seen for blood pressure or heart rate following repeat daily dosing 24-hours apart for up to 16 days. In an open-label ambulatory blood pressure monitoring study of 127 premenopausal women receiving bremelanotide once daily, there was a mean increase of 1.9 mmHg (95% CI: 1.0 to 2.7) in daytime systolic blood pressure (SBP) and a mean increase of 1.7 mmHg (95% CI: 0.9 to 2.4) in daytime diastolic blood pressure (DBP) after 8 days of dosing. The increase in SBP and DBP was transient with a mean peak effect in SBP of 2.8 mmHg between 4 to 8 hours post-dose and 2.7 mmHg for DBP at 0 to 4 hours post-dose. The increase in BP after 8 days of dosing was accompanied by a simultaneous and transient mean decrease in heart rate of 0.5 beats per minute (95% CI: -1.6 to -0.7). The SBP and DBP values 12 to 24-hours post-dose were similar to the predose values. Less than 1% of patients discontinued bremelanotide therapy for hypertension.1

Bremelanotide is a melanocortin receptor (MCR) agonist and binds to the MC1 receptor (MC1R). The MC1R is expressed on melanocytes; binding at this receptor leads to melanin expression and increased skin pigmentation. Focal skin hyperpigmentation has been reported in female patients receiving bremelanotide; patients with dark skin were more likely to develop this effect. In the phase 3 placebo-controlled trials, focal skin hyperpigmentation, including involvement of the face (melasma), gingiva, and breasts, was reported in 1% of patients who received up to 8 doses per month of bremelanotide compared to no placebo-treated patients. More than 8 doses per month of bremelanotide is not recommended. The risk of focal hyperpigmentation changes increases with chronic daily use of the drug. In another clinical study, 38% of patients developed focal hyperpigmentation after receiving bremelanotide daily for 8 days; among patients who continued bremelanotide for 8 more consecutive days, an additional 14% developed new focal pigmentary changes. Resolution of the focal hyperpigmentation was not confirmed in all patients after discontinuation of bremelanotide. Consider discontinuing bremelanotide if skin hyperpigmentation develops.1

Gastrointestinal-related adverse reactions are common with bremelanotide. Nausea was the most commonly reported adverse reaction, reported in 40% of bremelanotide-treated patients, and requiring anti-emetic therapy in 13% of bremelanotide-treated patients. The median onset of nausea was within 1-hour post-dose and lasted about 2 hours in duration. Nausea improves for most patients with the second dose; the incidence of nausea was highest after the first bremelanotide dose (reported in 21% of patients) then declined to about 3% after subsequent doses. Vomiting was reported in 4.8% of patients. Nausea (8%) and vomiting (1%) were among the most common adverse reactions leading to drug discontinuation during clinical trials. Pretreatment with oral ondansetron has been studied in a placebo-controlled trial of patients receiving bremelanotide; no significant difference in the incidence of bremelanotide-associated nausea was seen between the treatment groups. Less common GI adverse reactions occurring in less than 2% of bremelanotide-treated patients and at an incidence greater than in the placebo group were upper abdominal pain and diarrhea. Consider discontinuing bremelanotide for persistent or severe nausea or initiating anti-emetic therapy for those patients who are bothered by nausea but wish to continue with bremelanotide treatment.1

Injection site reaction, including injection site pain, unspecified injection site reactions, erythema, hematoma, pruritus, hemorrhage, bruising, paresthesia, and hypoesthesia have been reported in 13.2% of patients receiving bremelanotide. The study discontinuation rate due to injection site reaction with bremelanotide was 1%.1

In placebo-controlled trials, headache occurred at a higher incidence in bremelanotide-treated patients (11%) than placebo-treated patients. One patient experienced a headache event that was serious (intractable pain leading to hospitalization) and 1% of patients discontinued bremelanotide due to headache. Flushing also occurred more frequently in bremelanotide-treated patients (20%) than placebo-treated patients. None of the flushing events were serious and few were severe (less than 1%); only 1% of patients who received bremelanotide discontinued the drug due to flushing. The following additional common adverse reactions were reported in at least 2% of patients receiving bremelanotide and at an incidence greater than with placebo: fatigue (3.2%), hot flashes (2.7%), paresthesias (2.6%), and dizziness (2.2 %). Less common (less than 2%) adverse reactions in bremelanotide-treated patients included: myalgia, arthralgia, pain, restless leg syndrome, increased creatine phosphokinase, and pain in extremity.1

Cough (3.3%), nasal congestion (2.1%), and rhinorrhea (less than 2%) were reported patients receiving bremelanotide at an incidence greater than with placebo group. Less than 1% of clinical study subjects discontinued bremelanotide due to flu-like symptoms.1

A single case of acute hepatitis was reported in a patient who had received 10 doses of bremelanotide over 1 year. She presented with serum transaminases exceeding 40 times the upper limit of normal (ULN), total bilirubin 6 times the ULN, and alkaline phosphatase less than 2 times ULN. Liver tests returned to normal 4 months after study drug discontinuation. Because another etiology was not identified, the role of bremelanotide could not definitively be excluded. There was no imbalance between treatment groups in serum transaminase outliers or other signals for hepatotoxicity in the clinical development program.1

Oxytocin

Some patients can experience a hypersensitive uterine reaction to the effects of oxytocin. Excessive doses can have the same effect. This can produce increased, hypertonic uterine contractions, possibly prolonged, resulting in a number of adverse reactions such as cervical laceration, postpartum hemorrhage, pelvic hematoma, and uterine rupture.11

Oxytocin-induced afibrinogenemia has been reported; it results in increased postpartum bleeding and can potentially be life-threatening. Neonatal retinal hemorrhage has been reported. Also, intracranial bleeding including subarachnoid hemorrhage has been reported in patients receiving oxytocin.11 In one case, subarachnoid hemorrhage mimicked acute water intoxication and delayed the diagnosis of hemorrhage after an oxytocin assisted labor.12

Adverse maternal cardiovascular effects from oxytocin may include arrhythmia exacerbation, premature ventricular contractions (PVCs), and hypertension. In the fetus or neonate, fetal bradycardia, PVCs, and other arrhythmias have been noted.11

Oxytocin has an antidiuretic effect, and severe and fatal water intoxication has been noted and may occur if large doses (40—50 milliunits/minute) are infused for long periods. For example, water intoxication with seizures and coma has occurred in association with a slow oxytocin infusion over a 24-hour period. Management of water intoxication includes immediate oxytocin cessation and supportive therapy. In the fetus or neonate, fetal death, permanent CNS or brain damage, and neonatal seizures have been noted with oxytocin.11 The rare complications of blurred vision, ocular hemorrhage (of the conjunctiva), and pulmonary edema have been associated with oxytocin induced water intoxication.

Oxytocin administration has been associated with anaphylactoid reactions.11

Oxytocin-induced labor has been implicated in an increased incidence of neonatal hyperbilirubinemia, about 1.6 times more likely than after spontaneous labor. This can lead to neonatal jaundice.11

Nausea and vomiting have been noted with oxytoxin.11

Side effects that you should report to your doctor or health care professional as soon as possible:

allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
breathing problems
excessive or continuing vaginal bleeding
fast, irregular heartbeat
feeling faint or lightheaded, falls
high blood pressure
seizures
unusual bleeding or bruising
unusual swelling, sudden weight gain

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):

headache
nausea and vomiting.

This list may not include all possible adverse reactions or side effects. 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, a swollen painful area/areas on the leg.

Tadalafil

Back pain; dizziness; flushing; headache; indigestion; muscle aches; nausea; stuffy or runny nose. This list may not describe all possible side effects. Call your healthcare provider immediate if you experience signs of an allergic reaction like skin rash, itching or hives, swelling of the face, lips, or tongue; breathing problems; changes in hearing; changes in vision; chest pain; erection lasting more than 4 hours; fast, irregular heartbeat; seizures.

Adverse reactions to tadalafil for the treatment of erectile dysfunction (ED) were evaluated based on worldwide clinical trials of tadalafil involving over 5700 men (mean age 59, range 22 to 88 years). Over 100 patients were treated for 1 year or longer and over 1300 were treated for 6 months or more. During placebo-controlled trials, the discontinuation rate for patients treated with tadalafil (10 or 20 mg) was 3.1% compared to 1.4% in placebo-treated patients. In the treatment of patients with elevated pulmonary arterial pressures (PAH), adverse reactions to tadalafil were evaluated based on worldwide clinical trials involving 398 patients; 311 patients were treated for at least 182 days and 251 patients were treated for at least 360 days. During placebo-controlled trials, the overall rate of discontinuation due to an adverse event was higher in placebo-treated patients than in patients treated with tadalafil 40 mg/day (15% vs. 9%, respectively). In addition, the rate of discontinuation due to an adverse event not related to worsening of PAH was 5% in placebo-treated patients compared to 4% in patients treated with tadalafil 40 mg/day. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the rate of discontinuation due to an adverse effect was 3.6% of tadalafil-treated patients versus 1.6% of placebo-treated patients, and the mean age of study participants was 63 years.6 7

During clinical trials, hypotension was reported in < 2% and hypertension was reported in 1—3% of all tadalafil recipients. The risk for serious hypotension is augmented by the use of nitrates; therefore, the use of tadalafil in patients receiving nitrate therapy is contraindicated. Other cardiac effects reported in less than 2% of patients during clinical trials include angina, chest pain (unspecified), myocardial infarction, orthostatic hypotension, palpitations, syncope, and sinus tachycardia. Sudden cardiac death, stroke, chest pain, palpitations, and sinus tachycardia have all been noted in post-marketing experience with tadalafil. Most of the affected patients had pre-existing cardiovascular risk factors. Many of these events occurred during or shortly after sexual activity. In some cases, the symptoms occurred hours to days after the use of tadalafil and sexual activity.6 7 The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was non-inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure (hypotension) were observed, consistent with the augmentation by tadalafil of the blood-pressure-lowering effects of nitrates. In addition, tadalafil (20 mg) had no significant effect on supine or standing systolic and diastolic blood pressure in healthy male subjects compared to placebo; there was also no significant effect on heart rate.

The effect of a single 100-mg dose of tadalafil on QT prolongation was evaluated at the time of peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide)-controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc for tadalafil, relative to placebo, was 2.8 milliseconds using Individual QT correction and 3.5 milliseconds using Fridericia QT correction. A 100-mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with a 100-mg dose of tadalafil compared to placebo was 3.1 beats per minute.6 7

During clinical trials, adverse reactions occurring = 2% of patients with erectile dysfunction, = 9% of patients with pulmonary arterial hypertension, and more frequently in the tadalafil-treated groups than placebo included back pain (2—12%), myalgia (1—14%), and pain in limb (1—3%). Adverse musculoskeletal reactions reported in < 2% of tadalafil recipients included arthralgia and neck pain. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following musculoskeletal effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: back pain (2.4% vs 1.4%), extremity musculoskeletal pain (1.4% vs 0%), and myalgia (1.2% vs 0.3%). Adverse musculoskeletal effects reported in less than 1% of patients included arthralgia and muscle spasms. Myalgia lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia was described as diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. Generally, pain was reported as mild or moderate in severity and resolved without medical treatment; severe back pain was reported infrequently. When medical treatment was needed, acetaminophen or NSAIDs were generally effective; however, in a small number of patients who required treatment, a mild narcotic (e.g., codeine) was used. Overall, approximately 0.5% of all tadalafil-treated patients discontinued treatment due to back pain/myalgia. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no medically significant underlying pathology.6 7

Headache occurred in 3—15% of patients during erectile dysfunction clinical trials and in 32—42% of patients during pulmonary arterial hypertension clinical trials; headache was reported more frequently in the tadalafil-treated groups than placebo. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following centrally-mediated effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: headache (4.1% vs 2.3%) and dizziness (1% vs 0.5%). Headache lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. Adverse reactions reported in < 2% of tadalafil recipients during clinical trials and affecting the nervous system included hypoesthesia, insomnia, dizziness, paresthesias, vertigo, and somnolence or drowsiness. Migraine, transient global amnesia, seizures, and seizure recurrence have been reported during post-marketing use of tadalafil; due to the voluntary nature of the reports, the frequency of post-marketing adverse reactions is unknown and causality to the drug has not been established.6 7

Dyspepsia occurred in 1—10% of patients during erectile dysfunction (ED) clinical trials and in 10—13% of patients in pulmonary arterial hypertension clinical trials; dyspepsia was reported more frequently in the tadalafil-treated groups than placebo. Other gastrointestinal/digestive adverse reactions reported by tadalafil recipients and more frequently than placebo included nausea (1—11%), viral gastroenteritis (3—5%), gastroesophageal reflux (1—3%), abdominal pain (1—2%), and diarrhea (1—2%). During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following gastrointestinal effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: dyspepsia (2.4% vs 0.2%) and diarrhea (1.4% vs 1%). Adverse GI reactions reported in less than 1% of patients included gastroesophageal reflux disease, upper abdominal pain, nausea, and vomiting. Upper abdominal pain lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. Dysphagia, elevated hepatic enzymes, esophagitis, gastritis, vomiting, increased GGTP, loose stools, upper abdominal pain, hemorrhoidal hemorrhage, rectal hemorrhage, and xerostomia were reported in < 2% of patients treated with tadalafil during clinical trials.6 7

Nasal congestion occurred in 2—4% of patients during erectile dysfunction clinical trials and in 9% of patients during pulmonary arterial hypertension clinical trials; nasal congestion was reported more frequently in the tadalafil-treated groups than placebo. In addition, pharyngitis (reported as nasopharyngitis, 1—13%), upper and lower respiratory tract infection (3—13%), influenza (2—5%), cough (2—4%), bronchitis (2%), and urinary tract infection (2%) were reported in tadalafil-treated patients during clinical trials. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, nasopharyngitis occurred more frequently in tadalafil-treated patients (2.1%) than placebo-treated patients (1.6%). Dyspnea, epistaxis, and pharyngitis were reported in less than 2% of patients in clinical trials.6 7

Flushing occurred in 1—3% of patients during erectile dysfunction clinical trials and in 6—13% of patients during pulmonary arterial hypertension clinical trials; flushing was reported more frequently in the tadalafil-treated groups than those groups receiving placebo.6 7

During clinical trials, blepharedema or swelling of the eyelids, conjunctivitis, increased lacrimation, and ocular pain were reported in < 2% of tadalafil recipients.13 6

Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (n=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (< 0.1% of patients). Post-marketing reports have included cases of visual impairment such as retinal vein occlusion and visual field defects. Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors.14 15 16 17 It is thought that the vasoconstrictive effect of phosphodiesterase inhibitors may decrease blood flow to the optic nerve, especially in patients with a low cup to disk ratio. Symptoms, such as blurred vision (< 2%) and loss of visual field in one or both eyes, are usually reported within 24 hours of use. Most, but not all, of these patients who reported this adverse effect had underlying anatomic or vascular risk factors for development of NAION. These risk factors include, but are not limited to: low cup to disc ratio ('crowded disc'), age over 50 years, diabetes, high blood pressure, coronary artery disease, hyperlipidemia, and smoking. Additionally, two patients had retinal detachment and one patient had hypoplastic optic neuropathy.14 It is not yet possible to determine if these adverse events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.6 7

Adverse reactions affecting hearing or otic special senses and occurring in < 2% of patients in controlled clinical trials of tadalafil include hearing loss and tinnitus. In addition, 29 reports of sudden changes in hearing including hearing loss or decrease in hearing, usually in 1 ear only, have been reported to the FDA during post-marketing surveillance in patients taking sildenafil, tadalafil, or vardenafil; the reports are associated with a strong temporal relationship to the dosing of these agents. Many times, the hearing changes are accompanied by vestibular effects including dizziness, tinnitus, and vertigo. Follow-up has been limited in many of the reports; however, in approximately one-third of the patients, the hearing loss was temporary. Concomitant medical conditions or patient factors may play a role, although risk factors for the onset of sudden hearing loss have not been identified. Patients should be instructed to promptly contact their physician if they experience changes in hearing.6 7

There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for PDE5 inhibitors, such as tadalafil. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. During clinical trial evaluation of tadalafil, genitourinary effects including increased erection, spontaneous penile erection, and renal impairment (unspecified) were reported in less than 2% of study patients receiving the drug.6 7

During clinical trial evaluation of tadalafil, the following general adverse events were reported in less than 2% of patients receiving tadalafil: asthenia, facial edema, fatigue, and pain (unspecified).6 7

During clinical trial evaluation of tadalafil, the following dermatologic effects were reported in less than 2% of study patients: pruritus, rash (unspecified), and hyperhidrosis. Stevens-Johnson syndrome, exfoliative dermatitis, and urticaria have all been noted in post-marketing experience with tadalafil. Due to the uncontrolled and voluntary nature of post-marketing reports, neither the frequency nor a definitive causal relationship to tadalafil can be established.6 7

Storage

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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