Black Box Warning

Embryo-Foetal Toxicity Do not administer macitentan to a pregnant female because it may cause foetal harm. Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for 1 month after stopping treatment by using acceptable methods of contraception.

Composition

Each film coated tablet contains

Macitentan……..10mg

Colours: Titanium Dioxide IP

Dosage Form

Tablets

Pharmacology

Pharmacodynamics

Mechanism of Action

Macitentan is an endothelin receptor antagonist (ERA) that prevents the binding of ET-1 to both ETA and ETB receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro.

Pharmacodynamics Pulmonary Haemodynamics

Patients treated with macitentan 10 mg (N=57) achieved a median reduction of 37% (95% CI: 22 to 49) in pulmonary vascular resistance and an increase of 0.6 L/min/m² (95% CI: 0.3 to 0.9) in the cardiac index compared with placebo (N=67).

Cardiac Electrophysiology

In a randomized, placebo-controlled, four-way crossover study with a positive control in healthy subjects, repeated doses of macitentan 10 and 30 mg (3 times the recommended dosage) had no significant effect on the QTc interval.

Pharmacokinetics

The pharmacokinetics of macitentan and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of macitentan is dose-proportional over a range from 1 mg to 30 mg after once-daily administration. A cross-study comparison shows that the exposures to macitentan and its active metabolite in patients with PAH are similar to those observed in healthy subjects.

Absorption and Distribution

The maximum plasma concentration of macitentan is achieved about 8 hours after oral administration. The absolute bioavailability after oral administration is not known. In a study in healthy subjects, the exposure to macitentan and its active metabolite were unchanged after a high-fat breakfast. Macitentan may, therefore, be taken with or without food. Macitentan and its active metabolite are highly bound to plasma proteins (>99%), primarily to albumin and to a lesser extent to alpha-1-acid glycoprotein. The apparent volumes of distribution (Vss/F) of macitentan and its active metabolite were about 50 L and 40 L, respectively, in healthy subjects.

Metabolism and Elimination

Following oral administration, the apparent elimination half-lives of macitentan and its active metabolite are approximately 16 hours and 48 hours, respectively. Macitentan is metabolized primarily by oxidative depropylation of the sulphamide to form the pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 (CYP) system, mainly CYP3A4 with a minor contribution of CYP2C19. At steady state in pulmonary arterial hypertension (PAH) patients, the systemic exposure to the active metabolite is 3 times the exposure to macitentan and is expected to contribute approximately 40% of the total pharmacologic activity. In a study in healthy subjects with radiolabelled macitentan, approximately 50% of radioactive drug material was eliminated in urine but none was in the form of unchanged drug or the active metabolite. About 24% of the radioactive drug material was recovered from the faeces.

Special Populations

There are no clinically relevant effects of age, sex, or race on the pharmacokinetics of macitentan and its active metabolite.

Renal Impairment

Exposure to macitentan and its active metabolite in patients with severe renal impairment (creatinine clearance [CrCl] 15 to 29 mL/min) compared to healthy subjects was increased by 30% and 60%, respectively. This increase is not considered clinically relevant.

Hepatic Impairment

Exposure to macitentan was decreased by 21%, 34% and 6%, and exposure to the active metabolite was decreased by 20%, 25% and 25% in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, and C), respectively. This decrease is not considered clinically relevant.

Indications

OPSUTAN Tablets are indicated for the treatment of PAH (WHO Group I) to delay disease progression.

Disease progression included death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment).

Macitentan also reduces hospitalization for PAH.

Dosage and Administration

The recommended dosage of OPSUTAN Tablets is 10 mg once daily for oral administration. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended.

OPSUTAN Tablets should be taken every day at about the same time. If the patient misses a dose of OPSUTAN Tablets, the patient should be told to take it as soon as possible and then take the next dose at the regularly scheduled time. The patient should be told not to take two doses at the same time if a dose has been missed.

Pregnancy Testing in Females of Reproductive Potential

Initiate treatment with OPSUTAN Tablets in females of reproductive potential only after a negative pregnancy test. Obtain a monthly pregnancy test during treatment.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients
• Pregnancy
• Macitentan is contraindicated in females who are pregnant. If macitentan is used during     pregnancy, apprise the patient of the potential hazard to the foetus.
• Women of childbearing potential who are not using reliable contraception
• Breastfeeding
• Patients with severe hepatic impairment (with or without cirrhosis)
• Baseline values of hepatic aminotransferases (aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT) >3 × ULN)

Warnings and Precautions

Embryo-Foetal Toxicity

Macitentan may cause foetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods and obtain monthly pregnancy tests.

Hepatotoxicity

ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. Macitentan is not to be initiated in patients with severe hepatic impairment or elevated aminotransferases (>3 × ULN), and is not recommended in patients with moderate hepatic impairment. Liver enzyme tests should be obtained prior to initiation of macitentan.

Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 x ULN, or by clinical symptoms of hepatotoxicity, discontinue macitentan.

Consider re-initiation of macitentan when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.

Fluid Retention

Peripheral oedema and fluid retention are known clinical consequences of PAH and known effects of ERAs. Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment.

Postmarketing cases of oedema and fluid retention occurring within weeks of starting macitentan, some requiring intervention with a diuretic or hospitalization for decompensated heart failure, have been reported.

Monitor for signs of fluid retention after macitentan initiation. If clinically significant fluid retention develops, evaluate the patient to determine the cause, such as macitentan or underlying heart failure, and the possible need to discontinue macitentan.

Haemoglobin Decrease

As with other ERAs, treatment with macitentan has been associated with a decrease in haemoglobin concentration. Cases of anaemia requiring blood cell transfusion have been reported with macitentan and other ERAs. Initiation of macitentan is not recommended in patients with severe anaemia. It is recommended that haemoglobin concentrations be measured prior to initiation of treatment and tests repeated during treatment as clinically indicated.

Pulmonary Oedema with Pulmonary Veno-occlusive Disease (PVOD)

Cases of pulmonary oedema have been reported with vasodilators (mainly prostacyclins) when used in patients with PVOD. Should signs of pulmonary oedema occur, consider the possibility of associated PVOD. If confirmed, discontinue macitentan.

Decreased Sperm Counts

Other ERAs have caused adverse effects on spermatogenesis. Male patients should be counselled about the potential effects on fertility.

Excipients

Macitentan tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Macitentan tablets contain lecithin derived from soya. If a patient is hypersensitive to soya, macitentan must not be used.

Drug Interactions

In vitro Studies

The CYP450 enzymes, CYP3A4, CYP2C8, CYP2C9 and CYP2C19, are involved in the metabolism of macitentan and formation of its metabolites. Macitentan and its active metabolite do not have clinically relevant inhibitory or inducing effects on CYP450 enzymes.

Macitentan and its active metabolite are not inhibitors of hepatic or renal uptake transporters at clinically relevant concentrations, including the organic anion-transporting polypeptides (OATP1B1 and OATP1B3).

Macitentan and its active metabolite are not relevant substrates of OATP1B1 and OATP1B3, but enter the liver by passive diffusion.

Macitentan and its active metabolite are not inhibitors of hepatic or renal efflux pumps at clinically relevant concentrations, including the multidrug-resistant protein (P-gp, MDR-1) and multidrug and toxin extrusion transporters (MATE1 and MATE2-K). Macitentan inhibits the breast cancer resistance protein (BCRP) at clinically relevant intestinal concentrations.

Macitentan is not a substrate for P-gp/MDR-1. At clinically relevant concentrations, macitentan and its active metabolite do not interact with proteins involved in hepatic bile salt transport, i.e. the bile salt export pump (BSEP) and the sodium-dependent taurocholate co-transporting polypeptide (NTCP).

In vivo Studies

Strong CYP3A4 Inducers

Strong inducers of CYP3A4 (such as rifampin, St. John’s wort, carbamazepine and phenytoin) significantly reduce macitentan exposure. Concomitant use of macitentan with strong CYP3A4 inducers should be avoided.

Strong CYP3A4 Inhibitors

Concomitant use of strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir and saquinavir) approximately double macitentan exposure. Many HIV drugs such as ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of macitentan with strong CYP3A4 inhibitors. Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment.

Warfarin

Macitentan, given as multiple doses of 10 mg once daily, had no effect on exposure to S-warfarin (CYP2C9 substrate) or R-warfarin (CYP3A4 substrate) after a single dose of 25 mg warfarin. The pharmacodynamic effect of warfarin on the International Normalized Ratio (INR) was not affected by macitentan. The pharmacokinetics of macitentan and its active metabolite were not affected by warfarin.

Sildenafil

At steady state, the exposure to sildenafil 20 mg t.i.d. was increased by 15% during concomitant administration of macitentan 10 mg once daily. Sildenafil, a CYP3A4 substrate, did not affect the pharmacokinetics of macitentan, while there was a 15% reduction in the exposure to the active metabolite of macitentan. These changes are not considered clinically relevant.

Cyclosporine A

Concomitant treatment with cyclosporine A 100 mg b.i.d., a combined CYP3A4 and OATP inhibitor, did not alter the steady-state exposure to macitentan and its active metabolite to a clinically relevant extent.

Hormonal Contraceptives

Macitentan 10 mg once daily did not affect the pharmacokinetics of an oral contraceptive (norethisterone 1 mg and ethinyl oestradiol 35 ?g).

Use in Special Populations

Renal Impairment

Based on pharmacokinetic data, no dose adjustment is required in patients with renal impairment. There is no clinical experience with the use of macitentan in PAH patients with severe renal impairment.

The use of macitentan is not recommended in patients undergoing dialysis. Caution is recommended in this population. Patients with renal impairment may run a higher risk of experiencing hypotension and anaemia during treatment with macitentan. Therefore, monitoring of blood pressure and haemoglobin should be considered.

Hepatic Impairment

Based on pharmacokinetic data, no dose adjustment is required in patients with mild, moderate or severe hepatic impairment. However, there is no clinical experience with the use of macitentan in PAH patients with moderate or severe hepatic impairment. Macitentan must not be initiated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (greater than 3 times the upper limit of normal (>3 × ULN). Liver enzyme tests should be obtained prior to initiation of macitentan. If sustained, unexplained, clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 × ULN, or by clinical symptoms of liver injury (e.g. jaundice), macitentan treatment should be discontinued.

Pregnancy

Pregnancy Category X

Risk Summary

Macitentan may cause foetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Macitentan was teratogenic in rabbits and rats at all doses tested. A no-effect dose was not established in either species. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a foetus.

Lactation

It is not known whether macitentan is present in human milk. Macitentan and its metabolites were present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions from macitentan in nursing infants, nursing mothers should discontinue nursing or discontinue macitentan.

Paediatric Use

The safety and efficacy of macitentan in children has not been established.

Geriatric Use

No dose adjustment is required in patients over the age of 65 years. There is limited clinical experience in patients over the age of 75 years. Therefore, macitentan should be used with caution in this population.

Females and Males of Reproductive Potential

Females: Pregnancy Testing

Female patients of reproductive potential must have a negative pregnancy test prior to starting treatment with macitentan and monthly pregnancy tests during treatment with macitentan. Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Perform a pregnancy test if pregnancy is suspected for any reason. For positive pregnancy tests, counsel patients on the potential risk to the foetus.

Contraception

Female patients of reproductive potential must use acceptable methods of contraception during treatment with macitentan and for 1 month after treatment with macitentan. Patients may choose one highly effective form of contraception (intrauterine devices [IUD], contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counselling by another healthcare provider trained in contraceptive counselling.

Males: Testicular Effects

Like other ERAs, macitentan may have an adverse effect on spermatogenesis.

Undesirable Effects

Clinically significant adverse reactions that appear in other sections of the labelling include the following:

• Embryo-Foetal Toxicity
• Hepatotoxicity
• Fluid Retention
• Decrease in Haemoglobin

Clinical Trial Experience

Tabulated List of Adverse Reactions

Adverse reactions associated with macitentan obtained from the clinical study are tabulated below.

Frequencies are defined as very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

System organ class	Frequency	Adverse reaction
Infections and infestations	Very common	Nasopharyngitis
	Very common	Bronchitis
	Common	Pharyngitis
	Common	Influenza
	Common	Urinary tract infection
Blood and lymphatic system disorders	Very common	Anaemia
Immune system disorders	Uncommon	Hypersensitivity reactions (e.g. angio-oedema, pruritus, rash)
Nervous system disorders	Very common	Headache
Vascular disorders	Common	Hypotension
Respiratory, thoracic and mediastinal disorders	Common	Nasal congestion
General disorders and administration site conditions	Very common	Oedema, fluid retention

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of macitentan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Immune System Disorders: hypersensitivity reactions (angio-oedema, pruritus and rash).
• Respiratory, Thoracic and Mediastinal Disorders: nasal congestion.
• Gastrointestinal Disorders: elevations of liver aminotransferases (ALT, AST) and liver injury have been reported with macitentan use; in most cases, alternative causes could be identified (heart failure, hepatic congestion, autoimmune hepatitis).
• ERAs have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure.
• General Disorders and Administration Site Conditions: oedema/fluid retention. Cases of oedema and fluid retention occurred within weeks of starting macitentan, some requiring intervention with a diuretic, fluid management or hospitalization for decompensated heart failure.
• Cardiac Disorders: symptomatic hypotension.

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 180 3024.

By reporting side effects, you can help provide more information on the safety of this product.

Overdosage

Macitentan has been administered as a single dose of up to and including 600 mg to healthy subjects (60 times the approved dosage). Adverse reactions of headache, nausea and vomiting were observed. In the event of an overdose, standard supportive measures should be taken, as required. Dialysis is unlikely to be effective because macitentan is highly protein-bound.

Storage and Handling Instructions

Store below 30°C.

Packaging Information

OPSUTAN Tablets: Blister pack of 10 tablets

February 2018