Adempas

Adempas information, interactions and side effects, Adempas (riociguat) is a tablet for oral administration. Riociguat is methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1Hpyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl) carbamate with the following structural formula:

adempas

Riociguat is a white to yellowish, crystalline, non-hygroscopic substance with a molecular weight of 422.42 g/mol. In solid form it is stable to temperature, light, and humidity.

The solubility at 25°C in water: 4 mg/L, in ethanol: 800 mg/L, in 0.1 HCl (pH 1): 250 mg/L and in buffer (phosphate) pH 7: 3 mg/L. In the pH range of 2 to 4 the solubility showed strong pH-dependency. Solubility increases at lower pH values.

Each round film-coated tablet contains 0.5 mg (1.0, 1.5, 2.0, 2.5 mg) riociguat. The inactive ingredients are cellulose microcrystalline, crospovidone, hypromellose 5cP, lactose monohydrate, magnesium stearate, sodium laurylsulfate, hydroxypropylcellulose, hypromellose 3cP, propylene glycol, titanium dioxide. Adempas 1 mg, 1.5 mg, 2 mg and 2.5 mg tablets contain, in addition, ferric oxide yellow. Adempas 2 mg and 2.5 mg tablets contain, in addition, ferric oxide red.

INDICATIONS

Chronic-Thromboembolic Pulmonary Hypertension

Adempas is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class.

Pulmonary Arterial Hypertension

Adempas is indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening.

Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominately patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%).

DOSAGE AND ADMINISTRATION

Recommended Dosage In Adult Patients

The recommended starting dosage is 1 mg taken 3 times a day. For patients who may not tolerate the hypotensive effect of Adempas, consider a starting dose of 0.5 mg taken three times a day. If systolic blood pressure remains greater than 95 mmHg and the patient has no signs or symptoms of hypotension, up-titrate the dose by 0.5 mg taken three times a day. Dose increases should be no sooner than 2 weeks apart. The dose can be increased to the highest tolerated dosage, up to a maximum of 2.5 mg taken three times a day. If at any time, the patient has symptoms of hypotension, decrease the dosage by 0.5 mg taken three times a day.

Dosage Interruption

If a dose is missed, advise patients to continue with the next regularly scheduled dose. In case Adempas is interrupted for 3 days or more, re-titrate Adempas.

Pregnancy Testing In Females Of Reproductive Potential

Obtain pregnancy tests prior to initiation and monthly during treatment.

Use In Patients Who Smoke

Consider titrating to dosages higher than 2.5 mg three times a day, if tolerated, in patients who smoke. A dose decrease may be required in patients who stop smoking.

Strong CYP And P-gp/BCRP inhibitors

Consider a starting dose of 0.5 mg, three times a day when initiating Adempas in patients receiving strong cytochrome P450 (CYP) and P-glycoprotein/breast cancer resistance protein (P-gp/BCRP) inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (for example, ritonavir). Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors.

HOW SUPPLIED

Dosage Forms And Strengths

Tablets: film-coated, round, bi-convex:

  • 0.5 mg, white, with “BAYER” cross on one side and “0.5” and “R” on the other side
  • 1 mg, pale-yellow, with “BAYER” cross on one side and “1” and “R” on the other side
  • 1.5 mg, yellow-orange, with “BAYER” cross on one side and “1.5” and “R” on the other side
  • 2 mg, pale orange, with “BAYER” cross on one side and “2” and “R” on the other side
  • 2.5 mg, red-orange, with “BAYER” cross on one side and “2.5” and “R” on the other side

Storage And Handling

Adempas (riociguat) tablets are film-coated, round, and debossed with the “Bayer cross” on one side.

 

Color Debossing Side 2 NDC 50419-xxx-xx
Bottle of 90 Blister of 42
0.5 mg White 0.5 R 250-01 250-03
1 mg Pale yellow 1 R 251-01 251-03
15 mg Yellow-orange 1.5 R 252-01 252-03
2 mg Pale orange 2 R 253-01 253-03
2.5 mg Red-orange 2.5 R 254-01 254-03

 

Storage

Store at 25°C (77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F).

SIDE EFFECTS

The following serious adverse reactions are discussed elsewhere in the labeling:

  • Embryo-Fetal Toxicity
  • Hypotension
  • Bleeding

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described below reflect exposure to Adempas in two, randomized, double blind, placebo-controlled trials in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH patients (PATENT-1). The population (Adempas: n = 490; Placebo: n = 214) was between the age of 18 and 80 years.

The safety profile of Adempas in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH (PATENT-1) were similar. Therefore, adverse drug reactions (ADRs) identified from the 12 and 16 week placebo-controlled trials for PAH and CTEPH respectively were pooled, and those occurring more frequently on Adempas than placebo ( ≥ 3%) are displayed in Table 1 below. Most adverse reactions in Table 1 can be ascribed to the vasodilatory mechanism of action of Adempas.

The overall rates of discontinuation due to an adverse event in the pivotal placebo-controlled trials were 2.9% for Adempas and 5.1% for placebo (pooled data).

Table 1: Adverse Reactions Occurring More Frequently ( ≥ 3%) on Adempas than Placebo (Pooled from CHEST-1 and PATENT-1)

 

Adverse Reactions Adempas %
(n=490)
Placebo %
(n=214)
Headache 27 18
Dyspepsia and Gastritis 21 8
Dizziness 20 13
Nausea 14 11
Diarrhea 12 8
Hypotension 10 4
Vomiting 10 7
Anemia (including laboratory parameters) 7 2
Gastroesophageal reflux disease 5 2
Constipation 5 1

Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were: palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension and peripheral edema. With longer observation in uncontrolled long-term extension studies the safety profile was similar to that observed in the placebo controlled phase 3 trials.

DRUG INTERACTIONS

Pharmacodynamic Interactions With Adempas

Nitrates

Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated because of hypotension.

PDE Inhibitors

Co-administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline), is contraindicated because of hypotension. Clinical experience with co-administration of Adempas and other phosphodiesterase inhibitors (for example, milrinone, cilostazole, roflumilast) is limited.

Pharmacokinetic Interactions With Adempas

Smoking

Plasma concentrations in smokers are reduced by 50-60% compared to nonsmokers. Based on pharmacokinetic modeling, for patients who are smokers, doses higher than 2.5 mg three times a day may be considered in order to match exposure seen in nonsmoking patients. Safety and effectiveness of Adempas doses higher than 2.5 mg three times a day have not been established. A dose reduction should be considered in patients who stop smoking.

Strong CYP and P-gp/BCRP inhibitors

Concomitant use of riociguat with strong cytochrome CYP inhibitors and Pgp/BCRP inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (such as ritonavir) increase riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 3 times a day when initiating Adempas in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.

Strong CYP3A inducers

Strong inducers of CYP3A (for example, rifampin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may significantly reduce riociguat exposure. Data are not available to guide dosing of riociguat when strong CYP3A inducers are co-administered.

Antacids

Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption and should not be taken within 1 hour of taking Adempas.

PRECAUTIONS

Embryo-Fetal Toxicity

Adempas may cause fetal harm when administered during pregnancy and is contraindicated for use in women who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, advise use of acceptable contraception and obtain monthly pregnancy tests. For females, Adempas is only available through a restricted program under the Adempas REMS Program.

Adempas REMS Program

Females can only receive Adempas through the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program, a restricted distribution program.

Important requirements of the Adempas REMS Program include the following:

  • Prescribers must be certified with the program by enrolling and completing training.
  • All females, regardless of reproductive potential, must enroll in the Adempas REMS Program prior to initiating Adempas. Male patients are not enrolled in the Adempas REMS Program.
  • Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements.
  • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Adempas.
  • Further information, including a list of certified pharmacies, is available at www.AdempasREMS.com or 1-855-4 ADEMPAS.

Hypotension

Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors. Consider a dose reduction if patient develops signs or symptoms of hypotension.

Bleeding

In the placebo-controlled clinical trials, serious bleeding occurred in 2.4% of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage.

Pulmonary Veno-Occlusive Disease

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and, if confirmed, discontinue treatment with Adempas.

Patient Counseling Information

Embryo-Fetal Toxicity

Instruct patients on the risk of fetal harm when Adempas is used during pregnancy. Instruct females of reproductive potential to use effective contraception and to contact her physician immediately if they suspect they may be pregnant. Female patients must enroll in the Adempas REMS Program.

Adempas REMS Program

For female patients, Adempas is available only through a restricted program called the Adempas REMS Program. Male patients are not enrolled in the Adempas REMS Program.

Inform female patients (and their guardians, if applicable) of the following important requirements:

  • All female patients must sign an enrollment form.
  • Advise female patients of reproductive potential that she must comply with the pregnancy testing and contraception requirements.
  • 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.

Review the Medication Guide and REMS educational materials with female patients.

Other Risks Associated with Adempas
  • Inform patients of the contraindication of Adempas with nitrates or nitric oxide donors or PDE-5 inhibitors.
  • Advise patients about the potential risks/signs of hemoptysis and to report any potential signs of hemoptysis to their physicians.
  • Instruct patients on the dosing, titration, and maintenance of Adempas.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Carcinogenicity studies of riociguat were conducted in mice and rats. In mice, oral administration of riociguat (up to 25 mg/kg/day in males and 32 mg/kg/day in females) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 6 times the human’s exposure.

In rats, oral administration of riociguat (up to 20 mg/kg/day) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 7 times the human exposure.

Mutagenesis

Riociguat and M1 did not show genotoxic potential in the in vitro bacterial reverse mutation (Ames) assay, the in vitro chromosomal aberration assay in Chinese hamster V79 cells, or the in vivo micronucleus assay in the mouse.

Impairment of Fertility

In rats, no effects on male or female fertility were observed.

In male rats, oral administration of riociguat (up to 30 mg/kg/day) prior to and throughout the mating period had no effect on fertility. The no-effect dose for adverse effects is 37 times the human exposure when based on body surface area.

In female rats, oral administration of riociguat (up to 30 mg/kg/day) prior to and during mating and continuing to gestation Day 7 had no effect on fertility. The no-effect dose for adverse effects is 37 times the human exposure when based on body surface area.

Use In Specific Populations

Pregnancy

Pregnancy Category X

Risk Summary

Adempas may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Adempas was teratogenic and embryotoxic in rats at doses with exposures to unbound drug that were approximately 8 times and 2 times, respectively, the human exposure. In rabbits, riociguat led to abortions at 4 times the human exposure and fetal toxicity with exposures approximately 13 times the human exposure. If Adempas is used in pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

Animal Data

In rats administered riociguat orally (1, 5, and 25 mg/kg/day) throughout organogenesis, an increased rate of cardiac ventricular-septal defect was observed at the highest dose tested. The highest dose produced evidence of maternal toxicity (reduced body weight). Post-implantation loss was statistically significantly increased from the mid-dose of 5 mg/kg/day. Plasma exposure at the lowest dose in which no adverse effects were observed is approximately 0.4 times that in humans at the maximally recommended human dose (MRHD) of 2.5 mg three times a day based on area under the time-concentration curve (AUC) for unbound drug in rat and humans. Plasma exposure at the highest dose (25 mg/kg/day) is approximately 8 times that in humans at the MRHD while exposure at the mid-dose (5 mg/kg/day) is approximately 2 times that in humans at the MRHD. In rabbits given doses of 0.5, 1.5 and 5 mg/kg/day, an increase in spontaneous abortions was observed starting at the middle dose of 1.5 mg/kg, and an increase in resorptions was observed at 5 mg/kg/day. Plasma exposures at these doses were 4 times and 13 times, respectively, the human exposure at the MRHD.

Nursing Mothers

It is not known if Adempas is present in human milk. Riociguat or its metabolites were present in the milk of rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from riociguat, discontinue nursing or Adempas.

Pediatric Use

Safety and effectiveness of Adempas in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of Adempas, 23% were 65 and over, and 6% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Elderly patients showed a higher exposure to Adempas.

Females And Males Of Reproductive Potential

Pregnancy Testing

Female patients of reproductive potential must have a negative pregnancy test prior to starting treatment with Adempas, monthly during treatment, and one month after discontinuation of treatment with Adempas. Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Counsel patients on the risk to the fetus.

Contraception

Female patients of reproductive potential must use acceptable methods of contraception during treatment with Adempas and for 1 month after treatment with Adempas. 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 counseling by another healthcare provider trained in contraceptive counseling.

Renal Impairment

Safety and efficacy have not been demonstrated in patients with creatinine clearance < 15 mL/min or on dialysis

Hepatic Impairment

Safety and efficacy have not been demonstrated in patients with severe hepatic impairment (Child Pugh C).

OVERDOSE

In cases of overdose, blood pressure should be closely monitored and supported as appropriate. Based on extensive plasma protein binding, riociguat is not expected to be dialyzable.

CONTRAINDICATIONS

Pregnancy

Adempas may cause fetal harm when administered to a pregnant woman. Adempas is contraindicated in females who are pregnant. Adempas was consistently shown to have teratogenic effects when administered to animals. 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 the fetus.

Nitrates And Nitric Oxide Donors

Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated.

Phosphodiesterase Inhibitors

Concomitant administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline) is contraindicated.

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