Pulmonext Kit

Uses

Ambrisentan is used for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):

• To improve exercise ability and delay clinical worsening.
• In combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability.

Studies establishing effectiveness included predominantly patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%).

Tadalafil is used for the treatment of erectile dysfunction (ED).

Tadalafil is used for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).

Tadalafil is used for the treatment of erectile dysfunction and the signs of benign prostatic hyperplasia (ED/BPH).

Pulmonext Kit is also used to associated treatment for these conditions: Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)Benign Prostatic Hyperplasia (BPH), Erectile Dysfunction, Symptomatic pulmonary arterial hypertension (PAH)

How Pulmonext Kit works

Endothelin-1 (ET-1) is an endogenous peptide that acts on the endothelin type A (ETA) and endothelin type B (ETB) receptors in vascular smooth muscle and endothelium. ETA-mediated actions include vasoconstriction and cell proliferation, whereas ETB predominantly mediates vasodilation, anti-proliferation, and ET-1 clearance. In patients with pulmonary arterial hypertension, ET-1 levels are increased and correlate with increased right arterial pressure and severity of disease. Ambrisentan is one of several newly developed vasodilator drugs that selectively target the endothelin type A (ETA) receptor, inhibiting its action and preventing vasoconstriction. Selective inhibition of the ETA receptor prevents phospholipase C-mediated vasoconstriction and protein kinase C-mediated cell proliferation. Endothelin type B (ETB) receptor function is not significantly inhibited, and nitric oxide and prostacyclin production, cyclic GMP- and cyclic AMP-mediated vasodilation, and endothelin-1 (ET-1) clearance is preserved.

Penile erection during sexual stimulation is achieved by the relaxation of penile arteries and corpus cavernosal smooth muscles, leading to increased blood flow to the organ. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum, and is degraded by the cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum located around the penis. Tadalafil inhibits PDE5 and thereby enhances erectile function by increasing the amount of cGMP available.

Dosage

Pulmonext Kit dosage

Initial treatment is 5 mg once daily, and can be increased to 10 mg once daily if 5 mg is tolerated. Ambrisentan may be administered with or without food.

Erectile Dysfunction-

For Use as Needed:

• The recommended starting dose of Tadalafil for use as needed in most patients is 10 mg, taken prior to anticipated sexual activity.
• The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability. The maximum recommended dosing frequency is once per day in most patients.

For Once Daily Use:

• The recommended starting dose of Tadalafil for once daily use is 2.5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.
• The Tadalafil dose for once daily use may be increased to 5 mg, based on individual efficacy and tolerability.

Patients with BPH or with ED and BPH-

• Intimate for once daily use for BPH: The recommended dose of Intimate for once daily use is 5 mg, taken at approximately the same time every day.
• Intimate for once daily use for ED+BPH: The recommended dose of Intimate for once daily use is 5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.

Tadalafil may be taken without regard to food.

Side Effects

Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with Ambrisentan.

Body as a whole: hypersensitivity reactions including rash, urticaria, facial edema, Stevens-Johnson syndrome, and exfoliative dermatitis.

Cardiovascular and cerebrovascular: Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations, and tachycardia, may occur. Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. Hypotension (more commonly reported when tadalafil is given to patients who are already taking antihypertensive agents), hypertension, and syncope.

Skin and subcutaneous tissues: hyperhidrosis (sweating).

Gastrointestinal: abdominal pain and gastroesophageal reflux.

Nervous system: migraine, transient global amnesia.Respiratory system: epistaxis (nose bleed).

Special senses: blurred vision, nonarteritic anterior ischemic optic neuropathy, retinal vein occlusion, visual field defect.

Otologic: cases of sudden decrease or loss of hearing have been reported.

Toxicity

Ambrisentan is teratogenic and has a high risk of embryo-fetal toxicity. LD50 was found to be greater than or equal to 3160 mg/kg when studied in rats. There was no evidence of carcinogenic potential in 2 year oral daily dosing studies in rats and mice.

Oral, Rat LD₅₀ = 2000 mg/kg, no deaths or toxicity.

Precaution

Fluid Retention: Peripheral edema is a known class effect of endothelin receptor antagonists, and is also a clinical consequence of PAH and worsening PAH.

Pulmonary Veno-occlusive Disease: If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents such as Ambrisentan, the possibility of pulmonary veno-occlusive disease should be considered, and if con_rmed. Ambrisentan should be discontinued.

Hematological Changes: Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with Ambrisentan.

Cardiovascular: Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Potential for Drug Interactions When Taking Tadalafil for Once Daily Use Physicians should be aware that Tadalafil for once daily use provides continuous plasma Tadalafil levels and should consider this when evaluating the potential for interactions with medications (e.g., nitrates, alpha-blockers, anti-hypertensives and potent inhibitors of CYP3A4).

Prolonged Erection: There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. 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. Tadalafil should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease).

Eye & Sudden Hearing Loss: Physicians should advise patients to stop use of all PDE5 inhibitors, including Tadalafil, and seek medical attention in the event of a sudden loss of vision in one or both eyes & sudden decrease or loss of hearing.

Alpha blockers and Antihypertensives: Physicians should discuss with patients the potential for Tadalafil to augment the blood-pressure-lowering effect of alpha blockers and antihypertensive medications. Caution is advised when PDE5 inhibitors are coadministered with alpha blockers Renal Insufficiency, Hepatic Impairment, Consumption of alcohol.

Interaction

Multiple dose co-administration of Ambrisentan and Cyclosporine resulted in an approximately 2-fold increase in Ambrisentan exposure in healthy volunteers; therefore, limit the dose of Ambrisentan to 5 mg once daily when co-administered with Cyclosporine.

Volume of Distribution

Ambrisentan has a low distribution into red blow cells, with a mean blood:plasma ratio of 0.57 and 0.61 in males and females, respectively.

• 63 L

Elimination Route

Ambrisentan is rapidly absorbed with peak plasma concentrations occuring around 2 hours after oral administration. Cmax and AUC increase proportionally with dose across the therapeutic dosing range. Absolute oral bioavailability of ambrisentan is unknown. Absorption is not affected by food.

After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined.

Half Life

Ambrisentan has a terminal half-life of 15 hours. It is thought that steady state is achieved after around 4 days of repeat-dosing.

17.5 hours

Clearance

The mean oral clearance of ambrisentan was found to be 38 mL/min in healthy subjects and 19 mL/min in patients with pulmonary artery hypertension.

• oral cl=2.5 L/hr

Elimination Route

Ambrisentan is primarily cleared by non-renal pathways. Along with its metabolites, ambrisentan is primarily found in the feces following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan.

Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).

Pregnancy & Breastfeeding use

Pregnancy Category X. It is not known whether Ambrisentan is excreted in human milk. Breastfeeding while receiving Ambrisentan is not recommended.

It is not indicated for use in newborn, children or women.

Contraindication

Ambrisentan may cause fetal harm when administered to a pregnant woman. Ambrisentan is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Pregnancy must be excluded before the initiation of treatment with Ambrisentan and prevented during treatment and for one month after stopping treatment. Ambrisentan is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF) including IPF patients with pulmonary hypertension (WHO Group 3).

Nitrates: Administration of tadalafil to patients who are using any form of organic nitrate, either regularly and/or intermittently, is contraindicated. In clinical pharmacology studies, tadalafil was shown to potentiate the hypotensive effect of nitrates.

Hypersensitivity Reactions: Tadalafil is contraindicated in patients with a known serious hypersensitivity to tadalafil. Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis.

Special Warning

Pediatric patients: Safety and effectiveness of Ambrisentan in pediatric patients have not been established.

Hepatic impaired patient: Ambrisentan is not recommended in patients with moderate or severe hepatic impairment.

Renal Insufficiency-

For Use as Needed:

• Mild (creatinine clearance 51 to 80 mL/min): No dose adjustment is required.
• Moderate (creatinine clearance 31 to 50 mL/min): A starting dose of 5 mg not more than once per day is recommended, and the,maximum dose should be limited to 10 mg not more than once in every 48 hours.
• Severe (creatinine clearance <30 mL/min and on hemodialysis): The maximum recommended dose is 5 mg not more than once in every 72 hours.

For Once Daily Use:

• Mild (creatinine clearance 51 to 80 mL/min): No dose adjustment is required. Moderate (creatinine clearance 31 to 50 mL/min): No dose adjustment is required.
• Severe (creatinine clearance <30 mL/min and on hemodialysis): Tadalafil for once daily use is not recommended.

Hepatic Impairment-

For Use as Needed:

• Mild or moderate: The dose should not exceed 10 mg once per day.
• Severe: Not recommended

For Once Daily Use:

• Mild or moderate: Tadalafil for once daily use has not been extensively evaluated in patients with hepatic insufficiency. Therefore, caution is advised if Tadalafil for once daily use is prescribed to these patients.
• Severe: Not recommended.

Geriatrics:

No dose adjustment is required in patients >65 years of age

Acute Overdose

Adverse events were similar to those seen at lower doses. In case of overdose, standard supportive measure should be adopted as required

Storage Condition

Store in a cool and dry place, below 30° C. Protect from light and moisture.

Store below 30° C. Protect from light and moisture. Keep out of reach of children.

Innovators Monograph

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