Silkay

Pharmacotherapeutic Group: Endothelin Receptor Antagonist; Vasodilator.
Pharmacology: Pharmacodynamics: Mechanism of Action: Endothelian receptor antagonist that blocks endothelin receptors on endothelium and vascular smooth muscle (stimulation of these receptors is associated with vasoconstriction). Bosentan blocks both ET_A and ET_B receptors, with a slightly higher affinity for the A subtype.
Pharmacokinetics: Distribution: Vd: ~18 L (does not distribute into RBCs).
Protein binding, plasma: >98% primarily to albumin.
Metabolism: Hepatic via CYP2C9 and 3A4 to three primary metabolites (one contributing ~10% to 20% pharmacologic activity); steady-state plasma concentrations are 50% to 65% of those attained after single dose (most likely due to autoinduction of liver enzymes); steady-state is attained within 3 to 5 days.
Bioavailability: ~50%
Half-life elimination: ~5 hours; prolonged with heart failure, possibly in PAH.
Time to peak, plasma: 3 to 5 hours.
Excretion: Feces (as metabolites); urine (<3% as unchanged drug).

Pulmonary arterial hypertension: Treatment of pulmonary artery hypertension (PAH) (WHO Group I) in patients with WHO/NYHA Class II, III, or IV symptoms to improve exercise capacity and decrease the rate of clinical deterioration.
Note: According to treatment guidelines from the Fifth World Symposium on Pulmonary Hypertension (WSPH), only a small number of PAH patients with WHO-FC IV symptoms (ie, severely ill patients) were included in clinical trials, therefore, most experts consider bosentan second-line therapy in these patients.

Adult & Geriatric: Pulmonary artery hypertension: Oral: <40 kg: Initial and maintenance: 62.5 mg twice daily.
≥40 kg: Initial: 62.5 mg twice daily for 4 weeks; increase to maintenance dose of 125 mg twice daily.
Doses >125 mg twice daily do not appear to confer additional clinical benefit but may increase risk of liver toxicity.
Note: When discontinuing treatment, consider a reduction in dosage to 62.5 mg twice daily for 3 to 7 days (to avoid clinical deterioration).
Missed doses: If a dose is missed, administer as soon as remembered; if it is almost time for the next dose, take at the usual scheduled time. Do not administer a double dose to make up for a missed dose.
Coadministration with ritonavir (US labeling): Oral: Note: the Canadian labeling recommends the following dose adjustments with coadministration of any protease inibitor): Dosage adjustment for concurrent use with ritonavir: Coadministration of bosentan in patients currently receiving ritonavir for at least 10 days: Begin with bosentan 62.5 mg once daily or every other day based on tolerability.
Coadministration of ritonavir in patients currently receiving bosentan: Discontinue bosentan 36 hours prior to initiation of ritonavir. After at least 10 days of the protease inhibitor regimen, resume bosentan 62.5 mg once daily or every other day based on tolerability.
Pediatric: Pulmonary artery hypertension: Oral: US labeling: Children >12 years and Adolescents: Refer to adult dosing.
Canadian labeling: Children ≥3 years and Adolescents (based on limited data): 10 to 20 kg: Initial: 31.25 mg once daily for 4 weeks: increase to maintenance dose of 31.25 mg twice daily.
Renal impairment: No dosage adjustment necessary. Bosentan is unlikely to be removed by dialysis (due to high molecular weight and extensive plasma protein binding).
Hepatic impairment: Hepatic impairment of treatment initiation: Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate to severe impairment (Child-Pugh class B and C) and/or baseline transaminase >3 times ULN; Use should be avoided; systemic exposure is significantly increased in patients with moderate impairment (not studied in patients with severe impairment).
Hepatotoxicity during treatment: Modification based on transaminase elevation: Transaminase elevations accompanied by clinical symptoms of hepatic injury (unusual fatigue, nausea, vomiting, abdominal pain, fever, or jaundice) or a serum bilirubin ≥2 times ULN; Discontinue treatment.
AST/ALT >3 times but ≤5 times ULN: Confirm with additional tests; if confirmed, reduce dose to 62.5 mg twice daily or interrupt treatment and monitor at least every 2 weeks. If transaminase levels return to pre-treatment values, may continue or reintroduce treatment (at the starting dose), as appropriate. When reintroducing treatment, recheck transaminases within 3 days and at least every 2 weeks thereafter.
AST/ALT >5 times but ≤8 times ULN: Confirm with additional test; if confirmed, stop treatment. Monitor transaminase levels at least every 2 weeks. If transaminase levels return to pretreatment values, may reintroduce treatment (at the starting dose) as appropriate. Following reinitiation, recheck within 3 days and at least every 2 weeks thereafter.
AST/ALT >8 times ULN: Stop treatment and do not reintroduce.
Dietary Considerations: Avoid grapefruit and grapefruit juice.
Administration: May be administered with or without food, once in the morning and once in the evening.
Dosage forms: Tablet, Oral: 125 mg.

Hypersensitivity to bosentan or any component of the formulation; concurrent use of cyclosporine or glyburide; use in women who are or may become pregnant.
Canadian labeling: Additional contraindications (not in U.S. labeling): Moderate to severe hepatic impairment and/or baseline ALT or AST >3 times the upper limit of normal (ULN), particularly when total bilirubin >2 times ULN.

Bosentan is associated with transaminase elevations (ALT or AST ≥3 times ULN), and in a small numer of cases may occur with elevations in bilirubin. Monitor transaminases at baseline then monthly thereafter. Adjust dosage if elevations in liver enzymes occur without symptoms of hepatic injury or elevated bilirubin. In the postmarketing surveillance (with close monitoring), there have been rare cases of unexplained hepatic cirrhosis after prolonged therapy (>12 months) patients with multiple comorbidities and drug therapies. There have also been cases of hepatic failure. Treatment should be stopped in patients who develop elevated transaminases either in combination with symptoms of hepatic injury (unusual fatigue, jaundice, nausea, vomiting abdominal pain, and/or fever) or elevated bilirubin (≥2 times ULN); safety of reintroduction is unknown. Avoid use in patients with base line serum transaminases >3 times ULN at baseline (monitoring for hepatotoxicity may be more difficult) or moderate-to-severe hepatic impairment. The combination of hepatocellular injury (transaminase elevations >3 times ULN) and bilirubin increased ≥2 times ULN are a marker for potential serious hepatotoxicity. Transaminase elevations are dose dependent, generally asymptomatic, occur both early and late in therapy, progress slowly, and are usually reversible after treatment interruption or discontinuation. Transaminase elevations may also spontaneously reverse while continuing bosentan treatment. Consider the benefits of treatment versus the risk of hepatotoxicity when initiating therapy in patients with WHO Class II symptoms.
May cause birth defects (based on animal data); use in pregnancy is contraindicated. Exclude pregnancy prior to initiation of therapy and obtain pregnancy tests monthly during therapy and for 1 month after stopping treatment. Hormonal contraceptives (oral, injectable, transdermal, or implantable) should not be used as the sole means of contraception because they may not be effective in patients receiving bosentan. Patients with an intrauterine device (IUD) or tubal ligation do not need additional contraceptive measures.
Dose-related decreases in hematocrit/hemoglobin may be observed, usually within the first few weeks of therapy with subsequent stabilization of levels by 4 to 12 weeks of treatment. Monitor hemoglobin prior to initiation, after 1 and 3 months, and every 3 months thereafter. Significant decreases in hemoglobin require further evaluation to determine the cause and specific management. Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur. There have also been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization). If clinically significant fluid retention develops (with or without weight gain), further evaluation is necessary to determine cause and appropriate treatment or discontinuation of therapy. Use with caution in patients with underlying heart failure due to potential complications from fluid retention. In a scientific statement from the American Heart Association, bosentan has been determined to be an agent that may exacerbate underlying myocardial dysfunction. If signs of pulmonary edema occur, consider possibility of pulmonary veno-occlusive disease; may require discontinuation of bosentan. Hypersensitivity reactions, including rash and angioedema have been observed. Decreased sperm counts have been observed in men during treatment; bosentan may have an adverse effect on spermatogenesis. Potentially significant drug-drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy.

Monitoring Parameters: Serum transaminase (AST and ALT) and bilirubin (prior to treatment initiation and monthly thereafter, or more frequently if clinically necessary [every 2 weeks following transaminase elevations and 3 days after reintroducing therapy if withheld due to transaminase elevations]). Hemoglobin and hematocrit (at baseline, at 1 month and 3 months of treatment, and every 3 months thereafter [generally stabilizes after 4 to 12 weeks of treatment]).
Pregnancy test in women of childbearing potential (prior to the initiation of therapy and monthly thereafter, prior to shipment of monthly refill).
Monitor for clinical signs/symptoms of liver injury (eg, abdominal pain, fatigue, fever, jaundice, nausea, vomiting). Monitor for fluid retention.

Use in Pregnancy: May cause birth defects (based on animal data); use in pregnancy is contraindicated. Exclude pregnancy prior to initiation of therapy and obtain pregnancy tests monthly during treatment. Reliable contraception must be used during therapy and for 1 month after stopping treatment. Hormonal contraceptives (oral, injectable, transdermal, or implantable) should not be used as the sole means of contraception because they may not be effective in patients receiving bosentan. Patients with an intrauterine device (IUD) or tubal ligation do not need additional contraceptive measures. When a hormonal or barrier contraceptive is used, one additional method of contraception is still needed if a male partner has had a vasectomy. When initiating treatment for women of reproductive potential, a negative pregnancy test should be documented within the first 5 days of a normal menstrual period and ≥11 days after the last unprotected intercourse. A missed menses or suspected pregnancy should be reported to a healthcare provider and prompt immediate pregnancy testing. Sperm counts may be reduced in men during treatment. Women with pulmonary arterial hypertension (PAH) are encouraged to avoid pregnancy.
Use in Lactation: It is not known if bosentan is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.

Cardiovascular: Chest pain, edema, flushing, hypotension, palpitations, syncope.
Central nervous system: Headache.
Endocrine & metabolic: Fluid retention.
Hematologic & oncologic: Anemia, decreased hemoglobin (typically in first 6 weeks of therapy).
Hepatic: Increased serum ALT (dose-related), increased serum AST (dose-related).
Neuromuscular & skeletal: Arthralgia.
Respiratory: Respiratory tract infection, sinusitis.
Rare but important or life-threatening: Anaphylaxis, DRESS syndrome, fluid retention, hepatic cirrhosis (prolonged therapy), hepatic failure (rare), hypersensitivity reaction, leukopenia, neutropenia, severe anemia, skin rash, thrombocytopenia.

Metabolism/Transport effects: Substrate of CYP2C9 (minor), CYP3A4 (minor), SLCO1B1.
Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; induces CYP2C9 (weak/moderate), CYP3A4 (moderate).
Avoid Concomitant Use: Avoid concomitant use of Bosentan with any of the following: Antihepaciviral Combination Products; Asunaprevir; Axitinib; Bedaquiline; Bosutinib; Cobimetinib; Cyclosporine (systemic); Dasabuvir; Deflazacort; Elbasvir; Flibanserin; Glyburide; Grazoprevir; Nisoldipine; Olaparib; Ranolazine; Simeprevir; Sonidegib; Ulipristal; Velpatasvir; Venetoclax.
Increased Effect/Toxicity: Bosentan may increase the levels/effects of: Clarithromycin; ifosfamide.
The levels/effects of Bosentan may be increased by: Atazanavir; Boceprevir; Clarithromycin; Cobicistat; Cyclosporine (systemic); CYP2C9 Inhibitors (moderate); CYP2C9 inhibitors (strong); CYP3A4 inhibitors (moderate); CYP3A4 inhibitors (strong); Darunavir; Eltrombopag; Fosamprenavir; Gemfibrozil; Glyburide; Indinavir; Lopinavir; Nelfinavir; Phosphodiesterase 5 inhibitors; Rifampin; Ritonavir; Saquinavir; Telaprevir; Teriflunomide; Tipranavir.
Decreased Effect: Bosentan may decrease the levels/effects of: Antihepaciviral Combination Products: Asunaprevir; Atazanavir; Axitinib; Bedaquiline; Boceprevir; Bosutinib; Clarithromycin; Clozapine; Cobimetinib; Contraceptives (estrogens); Contraceptives (progestins); Cyclosporine (systemic); CYP3A4 Substrates; Daclatasvir; Darunavir; Dasabuvir; Deflazacort; Elbasvir; Estriol (systemic); Estriol (topical); Fentanyl; Filbanserin; Fosamprenavir; Glyburide; Grazoprevir; Guanfacine; Hydrocodone; Ibrutinib; Ifosfamide; Indinavir; Lopinavir; Lurasidone; Mirodefanil; Nelfinavir; Nimodipine; Nisoldipine; Olaparib; Palbociclib; Phosphodiesterase 5 inhibitors; Ranolazine; Rolapitant; Saquinavir; Saxagliptin; Simeprevir; Simvastatin; Sonidegib; Telaprevir; Tipranavir; Ulipristal; Velpatasvir; Venetoclax; Vitamin K antagonist; Zolpidem.
The levels/effect of Bosentan may be decreased by: Glyburide, rifampicin.
Food interactions: Bioavailability of bosentan is not affected by food. Bosentan serum concentrations may be increased by grapefruit juice. Management: Avoid grapefruit/grapefruit juice.

Storage/Stability: Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).

Other Antihypertensives

C02KX01 - bosentan ; Belongs to the class of other antihypertensives. Used in the treatment of pulmonary arterial hypertension.

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