Complete SPL Sections
WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY
BOXED WARNING SECTION
Because of the risk of hepatotoxicity, bosentan is available only through a restricted program called the Bosentan Risk Evaluation and Mitigation Strategy (REMS). Under the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Warnings and Precautions (5.2)]. Hepatotoxicity In clinical studies, bosentan caused at least 3-fold upper limit of normal (ULN) elevation of liver aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated bilirubin in a small number of cases. Because these changes are a marker for potential serious hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly [see Dosage and Administration (2.4), Warnings and Precautions (5.1)] . In the postmarketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (> 12 months) therapy with bosentan in patients with multiple comorbidities and drug therapies. There have also been reports of liver failure. The contribution of bosentan in these cases could not be excluded. In at least one case, the initial presentation (after > 20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of bosentan. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping bosentan with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction [see Dosage and Administration (2.4)]. Elevations in aminotransferases require close attention [see Dosage and Administration (2.4)] . Bosentan should generally be avoided in patients with elevated aminotransferases (> 3 x ULN) at baseline because monitoring for hepatotoxicity may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN, treatment with bosentan should be stopped. There is no experience with the reintroduction of bosentan in these circumstances. Embryo-Fetal Toxicity Bosentan is contraindicated for use during pregnancy because it may cause fetal harm if used by pregnant females based on animal data. Therefore, for females of reproductive potential, exclude pregnancy before the start of treatment with bosentan. Advise use of effective contraception before initiation, during treatment and for one month after stopping bosentan. When pregnancy is detected, discontinue bosentan as soon as possible [see Dosage and Administration (2.1), Contraindications (4.1), Warnings and Precautions (5.3), Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3)] .
1 INDICATIONS AND USAGE
INDICATIONS & USAGE SECTION
Bosentan is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%) [see Clinical Studies (14.1)] . in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability.
2 DOSAGE AND ADMINISTRATION
DOSAGE & ADMINISTRATION SECTION
3 DOSAGE FORMS AND STRENGTHS
DOSAGE FORMS & STRENGTHS SECTION
62.5 mg tablets: Orange white, round, biconvex film-coated tablet debossed with “945” on one side and plain on the other side. 125 mg tablets: Orange white, oval, biconvex film-coated tablet debossed with “946” on one side and plain on the other side.
4 CONTRAINDICATIONS
CONTRAINDICATIONS SECTION
5 WARNINGS AND PRECAUTIONS
WARNINGS AND PRECAUTIONS SECTION
6 ADVERSE REACTIONS
ADVERSE REACTIONS SECTION
The following important adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.1)] Embryo-fetal Toxicity [see Boxed Warning, Warnings and Precautions (5.3)] Fluid Retention [see Warnings and Precautions (5.4)]
7 DRUG INTERACTIONS
DRUG INTERACTIONS SECTION
8 USE IN SPECIFIC POPULATIONS
USE IN SPECIFIC POPULATIONS SECTION
10 OVERDOSAGE
OVERDOSAGE SECTION
Bosentan has been given as a single dose of up to 2,400 mg in normal volunteers, or up to 2,000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 mg and 1,000 mg twice daily of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. In the postmarketing period, there was one reported overdose of 10,000 mg of bosentan taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating, and blurred vision. He recovered within 24 hours with blood pressure support. Bosentan is unlikely to be effectively removed by dialysis due to the high molecular weight and extensive plasma protein binding.
11 DESCRIPTION
DESCRIPTION SECTION
Bosentan is an endothelin receptor antagonist that belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2’]-bipyrimidin-4-yl]-benzenesulfonamide monohydrate and has the following structural formula: Bosentan has a molecular weight of 569.63 and a molecular formula of C 27 H 29 N 5 O 6 S•H 2 O. Bosentan is a white to off-white crystalline powder. It is poorly soluble in water. In the solid state, bosentan is very stable, is not hygroscopic and is not light sensitive. Bosentan is available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: corn starch, ethylcellulose, glyceryl behenate, hydroxypropylmethylcellulose, iron oxide red, iron oxide yellow, magnesium stearate, povidone, pregelatinized maize starch, sodium starch glycolate, talc, titanium dioxide, and triacetin. Each bosentan 62.5 mg tablet contains 64.541 mg of bosentan monohydrate, equivalent to 62.5 mg of anhydrous bosentan. Each bosentan 125 mg tablet contains 129.082 mg of bosentan monohydrate, equivalent to 125 mg of anhydrous bosentan.
12 CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY SECTION
13 NONCLINICAL TOXICOLOGY
NONCLINICAL TOXICOLOGY SECTION
14 CLINICAL STUDIES
CLINICAL STUDIES SECTION
16 HOW SUPPLIED/STORAGE AND HANDLING
HOW SUPPLIED SECTION
62.5 mg film-coated, orange white, round, biconvex tablet debossed with “945” on one side and plain on the other side. Bottles of 60 with Child Resistant Closure.............................................................................NDC 47335-038-86 Blister pack of 30 (10 × 3) Tablets.........................................................................................NDC 47335-038-64 125 mg film-coated, orange white, oval, biconvex tablet debossed with “946” on one side and plain on the other side. Bottles of 60 with Child Resistant Closure............................................................................NDC 47335-039-86 Blister pack of 30 (10 × 3) Tablets.........................................................................................NDC 47335-039-64 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature]. Keep out of reach of children.
17 PATIENT COUNSELING INFORMATION
INFORMATION FOR PATIENTS SECTION
Advise the patient to read the FDA-approved patient labeling (Medication Guide) Restricted Access Advise the patient that bosentan is only available through a restricted access program called the Bosentan REMS and that bosentan is available only from certified pharmacies enrolled in the Bosentan REMS.. As a component of the Bosentan REMS, prescribers must review the contents of the bosentan Medication Guide with the patient before initiating bosentan and patients must sign the Patient Enrollment Form to confirm that they understand the risks of bosentan. Instruct patients that the risks associated with Bosentan include hepatotoxicity. Discuss with the patient the requirement to measure serum aminotransferases monthly [see Dosage and Administration (2.1, 2.4), Warnings and Precautions (5.1, 5.2)] . Embryo-Fetal toxicity Counsel female patients of reproductive potential about the need to use effective contraception prior to treatment, during treatment with bosentan and for one month after treatment discontinuation. Females of reproductive potential should have a negative pregnancy test prior to treatment [see Dosage and Administration (2.1), Warnings and Precautions (5.3), Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3)] . Patients should be instructed to immediately contact their physician if they suspect they may be pregnant. Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed. Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure. Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber. Lactation Advise women not to breastfeed during treatment with bosentan [see Use in Specific Populations (8.2)]. Infertility Advise males of reproductive potential that bosentan may impair fertility [see Warnings and Precautions (5.6), Adverse Reactions (6.1), Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. Other Risks Associated with Bosentan Instruct patients that the risks associated with bosentan also include the following: Decreases in hemoglobin and hematocrit – advise patients of the importance of hemoglobin testing Decreases in sperm count Fluid retention Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Manufactured by: Sun Pharmaceutical Industries Ltd. Survey No. 1012, Dadra-396 193, U.T. of D & NH and Daman & Diu, India.
SPL MEDGUIDE SECTION
SPL MEDGUIDE SECTION
Medication Guide Bosentan (boe-SEN-tan) Tablets Read the Medication Guide that comes with bosentan tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about bosentan tablets? Bosentan tablets can cause serious side effects including: Liver damage. Liver damage may not cause symptoms at first. Only a blood test can show if you have early liver damage. You must have your blood tested to check your liver function before you start bosentan tablets and each month after that. Your healthcare provider will order these tests. Regular blood tests are important because they will help your healthcare provider adjust or stop your treatment before there is permanent damage. Tell your healthcare provider if you have had liver problems, including liver problems while taking other medicines. Call your healthcare provider right away if you have any of these symptoms of liver problems while taking bosentan tablets: o nausea o vomiting o fever o unusual tiredness o stomach area (abdominal) pain o yellowing of the skin or the whites of your eyes (jaundice) Because of the risk for liver damage, bosentan tablets are only available through a restricted program called the Bosentan REMS. Before you begin taking bosentan tablets, you must read and agree to all of the requirements of the Bosentan REMS. Serious birth defects. Bosentan tablets can cause serious birth defects if taken during pregnancy. You should not be pregnant when you start taking bosentan tablets or during bosentan tablets treatment. Serious birth defects from bosentan tablets may happen early in pregnancy. Females who are able to get pregnant should have a negative pregnancy test before starting treatment with bosentan tablets. o Talk to your healthcare provider about your menstrual cycle. Your healthcare provider will decide when to do a pregnancy test and will order a pregnancy test for you depending on your menstrual cycle. o Females who are able to get pregnant are females who: have entered puberty, even if they have not started their menstrual period, and have a uterus, and have not gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed. o Females who are not able to get pregnant are females who: have not yet entered puberty, or do not have a uterus, or have gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed or are infertile for other medical reasons and this infertility is permanent and cannot be reversed. Females who are able to get pregnant should use effective birth control prior to starting treatment with bosentan tablets, during treatment with bosentan tablets, and for one month after stopping bosentan tablets because the medicine may still be in the body. o Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about options for effective birth control that you may use to prevent pregnancy during treatment with bosentan tablets. o If you decide that you want to change the form of birth control that you use, talk with your healthcare provider or gynecologist to be sure that you choose another acceptable form of birth control. o Do not have unprotected sex. Talk to your healthcare provider or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your healthcare provider may talk with you about using emergency birth control. o Tell your healthcare provider right away if you miss a menstrual period or think you may be pregnant. If you are the parent or caregiver of a female child who started taking bosentan tablets before reaching puberty, you should check your child regularly to see if she is developing signs of puberty. Tell your healthcare provider right away if you notice that she is developing breast buds or any pubic hair. Your healthcare provider should decide if your child has reached puberty. Your child may reach puberty before having her first menstrual period. See “What are the possible side effects of bosentan tablets?” for more information about side effects. What are bosentan tablets? Bosentan tablets are a prescription medicine used to treat people with certain types of pulmonary arterial hypertension (PAH), which is high blood pressure in the vessels of the lungs. Bosentan tablets can improve your ability to exercise and can slow the worsening of your physical condition and symptoms. Bosentan tablets lowers high blood pressure in your lungs and lets your heart pump blood more efficiently. Bosentan tablets are only: Prescribed by healthcare providers who are enrolled in the Bosentan REMS. Available to people who understand the risks and requirements and agree to enroll in the Bosentan REMS. Who should not take bosentan tablets? Do not take bosentan tablets if you: are pregnant, plan to become pregnant, or become pregnant during bosentan tablets treatment. Bosentan tablets can cause serious birth defects. All females should read the birth defects section of “What is the most important information I should know about bosentan tablets?” take any of these medicines: o cyclosporine A used to treat psoriasis and rheumatoid arthritis, and to prevent rejection of heart, liver, and kidney transplants o glyburide used to treat diabetes are allergic to bosentan or any of the ingredients in bosentan tablets. See the end of this Medication Guide for a complete list of the ingredients in bosentan tablets. If you have a rash, hives or your lips swell after taking bosentan tablets, it may be a sign of allergy. You should stop taking your bosentan tablets and talk to your healthcare provider. What should I tell my healthcare provider before taking bosentan tablets? Bosentan tablets may not be right for you. Tell your healthcare provider about all your medical conditions, including if you: have liver problems. are pregnant or plan to become pregnant. See “What is the most important information I should know about bosentan tablets?” are breast-feeding or plan to breast feed. Bosentan passes into your breast milk. It is not known if bosentan in breast milk can harm your baby. You and your healthcare provider should decide if you will take bosentan tablets or breastfeed. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Bosentan tablets and other medicines may affect how each other works and cause side effects. Especially tell your healthcare provider if you take: o hormone-based birth control, such as pills, shots, patches, and implants. These birth control methods may not work as well when taken with bosentan tablets. o simvastatin or other “-statin” medicines used to lower cholesterol o rifampin used for tuberculosis o ketoconazole, fluconazole, itraconazole, or voriconazole used for fungal infections o warfarin sodium used to prevent blood clots o ritonavir used to treat HIV There may be more than one brand name medicine. Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider or pharmacist when you get a new medicine. How should I take bosentan tablets? Your healthcare provider will give you detailed information about the Bosentan REMS. Bosentan tablets are only available through certified pharmacies. You will only receive a 30-day supply of bosentan tablets at one time. Take bosentan tablets exactly as prescribed. Your healthcare provider will tell you how much bosentan tablets to take and when to take it. In most ca...
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC 47335-038-86 Bosentan Tablets 62.5 mg Dispense the Medication Guide provided separately to each patient. Rx only 60 Tablets SUN PHARMA
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC 47335-038-64 Bosentan Tablets 62.5 mg For Hospital Use Only Dispense the Medication Guide provided separately to each patient. Rx only 30 Tablets (10 x 3 Unit-Dose) SUN PHARMA
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC 47335-039-86 Bosentan Tablets 125 mg Dispense the Medication Guide provided separately to each patient. Rx only 60 Tablets SUN PHARMA
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC 47335-039-64 Bosentan Tablets 125 mg For Hospital Use Only Dispense the Medication Guide provided separately to each patient. Rx only 30 Tablets (10 x 3 Unit-Dose) SUN PHARMA