Sandbox Riociguat

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# Black Box Warning

# Overview
Sandbox Riociguat is a Soluble Guanylate Cyclase Stimulator that is FDA approved for the treatment of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include fetal harm (teratogenic effects).

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
The recommended starting dosage is 1 mg taken 3 times a day. For patients who may not tolerate the hypotensive effect of Riociguat, 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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sandbox Riociguat in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Sandbox Riociguat in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of Adempas in pediatric patients have not been established.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sandbox Riociguat in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Sandbox Riociguat in pediatric patients.

# Contraindications

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

### PDE-5 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.

# Warnings

### Fetal Harm
- 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.

### Low Blood Pressure
- Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, left ventricular outflow tract obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors.

# Adverse Reactions

## Clinical Trials Experience
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.

## Postmarketing Experience
No postmarketing experience is currently available because Adempas was only recently approved by the FDA in 2013.

# Drug Interactions

### 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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): X
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.
Pregnancy Category (AUS): D
"While no increase in malformation rate was observed in the rabbit embryofetal development study, exaggerated pharmacological effects of riociguat on the F1 dams at  1.5 mg/kg/day led to an increased rate of abortion and total resorption. At the maternal and fetal NOAEL of 0.5 mg/kg/day the ERAUCU was similar to that expected clinically.
Riociguat prolonged the mean gestation time and reduced maternal bodyweight gain at the high dose (HD) of 15 mg/kg/day in the pre and postnatal development studies in rats (maternal NOAEL of 5 mg/kg/day, ERAUCU of about 1). A reduced number of live births were observed at doses  5 mg/kg/day but there were no notable effects on the development of the surviving pups including on their reproductive performance (NOAEL for pup development of 15 mg/kg/day, ERAUCU approximately 2 to 3).
The M1 metabolite BAY 60-4552 was not well tolerated in reproductive studies and the NOAEL for maternal and fetal toxicity was 2 mg/kg/day (ERAUCU <0.1). Doses of 5 mg/kg/day in rabbits resulted in increased rates of abortion. There was, however, no evidence of a direct teratogenic effect in either species." 

### Labor and Delivery
There are no guidelines for female patients undergoing labor and delivery because Adempas is contraindicated for pregnant women. The patient's risk should be reevaluated after delivery.

### 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, either discontinue nursing or Adempas.

### Pediatric Use
Safety and effectiveness of Adempas in pediatric patients have not been established. In growing rats, however, effects on bone formation were observed, including thickening of the growth plates, disorganized trabecular bone, and diffuse hyperostosis.

### Geriatic 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.

### Gender
Besides issues with pregnancy, there are no gender-specific guidelines for Adempas.

### Race
There are no race-specific guidelines for Adempas.

### 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).

### Females of Reproductive Potential and Males

### 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) , contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partners 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.

### Immunocompromised Patients
There are no guidelines for the use of Adempas in immunocompromised patients at this time.

# Administration and Monitoring

### Administration
Oral.

### Monitoring
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. Patient should also have blood pressure checked every two weeks to determine if a change in dosage is necessary.

# IV Compatibility
There is limited information regarding the compatibility of Adempas and IV administrations.

# Overdosage
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.

# Pharmacology

## Mechanism of Action
Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation. Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway. Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC via a different binding site, independently of NO. Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation. The active metabolite (M1) of riociguat is 1/3 to 1/10 as potent as riociguat.

## Structure
Adempas (riociguat) is a tablet for oral administration. Riociguat is methyl 4,6-diamino-2-pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate with the following structural formula:
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 25C 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, and titanium dioxide. Adempas 1, 1.5, 2 and 2.5 mg tablets contain, in addition, ferric oxide yellow. Adempas 2 and 2.5 mg tablets contain, in addition, ferric oxide red.

## Pharmacodynamics
There is a direct relationship between riociguat plasma concentration and hemodynamic parameters such as systemic vascular resistance, systolic blood pressure, pulmonary vascular resistance (PVR), and cardiac output.Hemodynamic parameters were assessed in CTEPH patients in CHEST-1. Right heart catheterization was performed at the beginning and the end of the study period in 233 patients. A statistically significant reduction of PVR (-246 dyn*s*cm-5) was shown in the Adempas group vs. placebo. Improvements in other hemodynamic parameters (not pre-specified as endpoints) are displayed in Table 2 below
Hemodynamic parameters were assessed in PAH patients in PATENT-1. Right heart catheterization was performed at the beginning and the end of the study period in 339 patients. A statistically significant reduction of PVR (-226 dyn*sec*cm-5) was shown in the Adempas individual titration group (to maximum dose of 2.5 mg three times a day) vs. placebo. Improvement in other relevant hemodynamic parameters (not pre-specified as endpoints) for the individual dose titration group versus placebo are displayed in Table 3

## Pharmacokinetics
Riociguat pharmacokinetics are dose proportional from 0.5 to 2.5 mg. Inter-individual variability of riociguat exposure (AUC) across all doses is approximately 60%, and within-subject variability is approximately 30%.

## Nonclinical Toxicology

### 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 humans 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.

# Clinical Studies

## Chronic-Thromboembolic Pulmonary Hypertension
A double-blind, multi-national, multi-center, study (CHEST-1) was conducted in 261 patients with CTEPH. Patients were included if they:
- were technically inoperable for pulmonary endarterectomy, with PVR >300 dyn*sec*cm-5 and mean pulmonary artery pressure >25 mmHg measured at least 90 days after the start of full anticoagulation, or
- had recurrent or persisting pulmonary hypertension defined as PVR > 300 dyn*sec*cm-5 measured at least 180 days following pulmonary endarterectomy.
Patients were randomized to Adempas titrated up to 2.5 mg three times a day (n=173) or placebo (n=88). All patients were initiated at 1 mg three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. The dose of riociguat was titrated every 2 weeks based on the patients systolic blood pressure and signs or symptoms of hypotension. Stable dosages of oral anticoagulants, diuretics, digitalis, calcium channel blockers and oxygen were allowed, but not concomitant therapy with NO donors, endothelin receptor antagonists, prostacyclin analogues (PCA), specific PDE-5 inhibitors (such as, sildenafil, tadalafil, or vardenafil), and nonspecific phosphodiesterase inhibitors (for example, dipyridamole or theophylline). The primary endpoint of the study was change from baseline in six minute walking distance (6MWD) after 16 weeks. The mean age of the patients enrolled was 59 years (range 1880 years). In the study, 72% of patients had inoperable CTEPH, 28% had recurrent or persisting pulmonary hypertension following pulmonary endarterectomy. The majority of patients had a World Health Organization (WHO) Functional Class II (31%) or III (64%) at baseline. The mean baseline 6MWD was 347 meters. In the study, 77% of patients were titrated to the maximum dose of 2.5 mg three times a day; 13%, 6%, 4%, and 1% of patients were titrated to riociguat doses of 2, 1.5, 1, and 0.5 mg three times a day, respectively. Results of the 6MWD over 16 weeks for the CHEST-1 study are shown in Figure 3.
The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 16 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. For deaths or clinical worsening without a termination visit or a measurement at that visit, the imputed worst value (zero) was used. Improvements in walking distance were apparent from Week 2 onward. At Week 16, the placebo adjusted mean increase in 6MWD within the Adempas group was 46 m (95% confidence interval : 25 m to 67 m; p<0.0001). For CHEST-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 39 m (95% CI, 25 m to 54 m). Figure 4 illustrates the results of the Adempas and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with Adempas benefit compared to those treated with placebo. As demonstrated in Figure 4, 143 patients receiving Adempas (83%) experienced an improvement in 6MWD compared to 50 patients (57%) on placebo.
Placebo-adjusted changes in 6MWD at 16 weeks were evaluated in subgroups (Figure 5) .
WHO Functional Class improvements in the CHEST-1 trial are shown in Table 4.

### Long Term Treatment of CTEPH
An open-label extension study (CHEST-2) included 237 patients who had completed CHEST-1. At the cut-off date in the CHEST-2 study, the mean treatment duration for the total population was 582 days ( 317). The probability of survival at 1 year and 2 years were 97% and 94%, respectively. Additionally, 6MWD and WHO Functional Class status appeared to further improve in patients taking Adempas. Without a control group, however, these data must be interpreted cautiously.

### Pulmonary Arterial Hypertension
A double-blind, multi-national, multi-center study (PATENT-1) was conducted in 443 patients with PAH as defined by PVR >300 dyn*sec*cm-5 and a PAP mean >25 mmHg. Patients were randomized to one of three treatment groups: Adempas titrated up to 1.5 mg (n=63), 2.5 mg (n=254) or placebo (n=126) three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. Patients assigned to Adempas were initiated at 1.0 mg three times a day. The dose of Adempas was up-titrated every 2 weeks based on the patients systolic blood pressure and signs or symptoms of hypotension. Oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed. In this study, 50% of the patients were treatment-naive with respect to PAH therapy, 44% were pre-treated with an endothelin receptor antagonist (ERA) and 6% were pre-treated with a PCA (inhaled, oral or subcutaneous). Pre-treated patients were defined as patients on stable treatment for 3 months with either an ERA or PCA; Adempas was added in combination to these background therapies. The primary endpoint of the study was change from baseline and placebo in 6MWD after 12 weeks in the 2.5 mg group. The mean age of all patients was 51 years and approximately 80% were female. PAH etiologies were either idiopathic (61%) or familial PAH (2%), PAH associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), or anorexigen or amphetamine use (1%). The majority of patients had a WHO Functional Class II (42%) or III (54%) at baseline. The overall mean baseline 6MWD was 363 meters. Approximately 75% of patients were up-titrated to receive the maximum dose of 2.5 mg three times a day by week 12; 15%, 6%, 3%, and 2% were titrated to doses of 2 mg, 1.5 mg, 1 mg, and 0.5 mg 3 times a day, respectively. Results of the 6MWD over 12 weeks for the PATENT-1 study are shown in Figure 6.
The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 12 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. In case of death or clinical worsening without a termination visit or a measurement at that termination visit, the imputed worst value (zero) was used. Figure 7 illustrates the results of the Adempas and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with Adempas benefit compared to those treated with placebo. As demonstrated in Figure 7, 193 patients receiving Adempas (76%) experienced an improvement in 6MWD compared to 74 patients (59%) on placebo.
Improvements 6MWD were apparent from Week 2 onward. At Week 12, the placebo-adjusted mean increase in 6MWD within the Adempas group was 36 m (95% CI: 20 m to 52 m; p<0.0001). For PATENT-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 29 m (95% CI, 17 m to 40 m).There was an exploratory 1.5 mg capped titration arm (n = 63). The data did not suggest incremental benefit from escalating dose from 1.5 mg three times a day to 2.5 mg three times a day. Placebo-adjusted changes in 6MWD at 12 weeks were evaluated in subgroups (Figure 8).
WHO Functional Class improvements in the IDT (individual dose titration) arm of the PATENT-1 trial are shown in Table 5.
Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6MWD and persistent worsening of WHO Functional Class. Effects of Adempas in PATENT-1 on events of clinical worsening are shown in Table 6.
Adempas-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p=0.0046; Stratified log-rank test). Significantly fewer events of clinical worsening up to week 12 (last visit) were observed in patients treated with Adempas (1.2%) compared to placebo (6.3%) (p=0.0285, Mantel-Haenszel estimate). The Kaplan-Meier plot of time to clinical worsening is presented in Figure 9.

### Long Term Treatment of PAH
An open label extension study (PATENT-2) included 363 patients who had completed PATENT-1. At the cut-off date in the PATENT-2 study, the mean treatment duration for the total population was 663 days ( 319). The probabilities of survival at 1 and 2 years were 97% and 93%, respectively. Without a control group, these data must be interpreted cautiously.

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

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

# Images

## Drug Images

## Package and Label Display Panel

# 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.
Females who are able to get pregnant must use two acceptable forms of birth control, during treatment with Adempas and for one month after stopping Adempas because the medicine may still be in the body. See the chart below for Acceptable Birth Control Options during treatment with Adempas.

### 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.
- Advise patients regarding activities that may impact the pharmacology of Adempas (strong multi pathway CYP inhibitors and P-gp/BCRP inhibitors and smoking). Patients should report all current medications and new medications to their physician.
- Advise patients that antacids should not be taken within 1 hour of taking Adempas.
- Inform patients that Adempas can cause dizziness, which can affect the ability to drive and use machines. They should be aware of how they react to Adempas, before driving or operating machinery and if needed, consult their physician.

# Precautions with Alcohol
Alcohol-Sandbox Riociguat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
Adempas

# Look-Alike Drug Names
There is limited information regarding Sandbox Riociguat Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price