Riociguat - Dosage, Indications, Contraindications, and Side Effects

Overview

Riociguat, a soluble guanylate cyclase stimulator, was developed by Bayer Healthcare Pharmaceuticals. It is used to treat pulmonary arterial hypertension (PAH), characterized by elevated blood pressure in the vessels that transport blood to the lungs, and also to treat chronic thromboembolic pulmonary hypertension (CTEPH), characterized by increased blood pressure in the lung arteries caused by blood clots which narrow or block the blood flow. Riociguat was approved by USFDA (United States Food and Drug Administration) on October 8th, 2013. It is known to improve the exercising ability in people with PAH and CTEPH and may also delay the worsening of symptoms in PAH. CTEPH and PAH are rare conditions, and Riociguat was considered an orphan medicine (a medicine used in rare diseases) by the European Medicines Agency on December 20th, 2007.

How Does Riociguat Work?

Cyclic guanosine monophosphate (cGMP) is a substance produced in response to nitric oxide by the lungs and other body parts by an enzyme called guanylate cyclase. This cGMP is responsible for relaxing and widening the blood vessels. Riociguat belongs to a class of medications called soluble guanylate cyclase (sGC) stimulators which work by relaxing and widening the blood vessels of the lungs to decrease pulmonary blood pressure and allow easy blood flow resulting in the ability to be more active.

Indications of Riociguat:

• Chronic Thromboembolic Pulmonary Hypertension: Riociguat is used in CTEPH to improve exercise ability after surgical treatment or in patients who cannot undergo surgery for CTEPH.

• Pulmonary Arterial Hypertension: Riociguat is used as a single drug or in combination with endothelin receptor antagonists or prostanoids.

Contraindications of Riociguat:

• Riociguat is contraindicated in pregnant women as it may cause fetal harm. In case the patient becomes pregnant during the treatment with Riociguat, the patient must be advised of the potential hazards to the fetus.

• Administration of Riociguat with nitrates and nitric oxide donors (Amyl nitrate) is contraindicated.

• Administration of Riociguat with specific PDE5 inhibitors (Sildenafil, Tadalafil) and non-specific PDE inhibitors is contraindicated.

• It is contraindicated in patients with pulmonary hypertension associated with idiopathic interstitial pneumonia (a respiratory disease that causes scarring of the lungs).

Dosage and Administration

Recommended Dosage in Adults: The recommended dose is 1 mg thrice daily. In the case of patients who cannot tolerate the hypotensive effect of Riociguat, a starting dose of 0.5 mg is advised three times a day. In cases of systolic blood pressure of more than 95mmHg, with no signs of hypotension, a gradual increase in dose is done by 0.5mg, taken thrice daily. The dose should not be increased no sooner than two weeks apart, and the highest tolerated dose is up to 2.5 mg, taken thrice daily, and if the patient experiences hypotension at any time, the dose is decreased by 0.5 mg thrice daily.

• If a dose is missed, the patients are asked to continue with the next scheduled dose; if interrupted for more than three days, re-titration (beginning from the lowest dose and gradually increasing it) should be done.

• In the case of females, pregnancy test reports are obtained before the initiation of treatment.

• In the case of people who smoke, titrating should be done at higher doses than 2.5 mg three times, if tolerated, and decreasing the dose when smoking is discontinued.

• In the case of patients receiving strong cytochrome P450 and P- glycoprotein or breast cancer resistance protein inhibitors or HIV protease inhibitors, a starting dose of 0.5 mg three times a day is initiated, along with monitoring the signs and symptoms of hypotension.

Warnings and Precautions

• Embryo-Fetal Toxicity: Riociguat may harm the fetus when administered to pregnant women. In females of reproductive potential, prior confirmation is taken before the drug administration, and monthly pregnancy test results are obtained. Reliable birth control methods must be used during the treatment for around one month after discontinuation of Riociguat.

• REMS Program: Under the Risk Evaluation and Mitigation Strategy (REMS) program, Riociguat is advised to females, which includes the following requirements:

• Prescribers and pharmacists are required to be certified with the program by enrollment and completion, following which they are authorized to prescribe or dispense Riociguat.

• All female patients, irrespective of reproductive potential, must enroll in the program and comply with pregnancy tests and contraception requirements before initiating treatment with Riociguat.

• Pulmonary Veno-Occlusive Disease (PVOD): Pulmonary vasodilators may worsen the cardiovascular status of patients with PVOD; hence Riociguat is not recommended for such patients. If signs of edema are seen, PVOD is suspected, and treatment with Riociguat is discontinued.

• Hypotension: Riociguat reduces the blood pressure in patients with hypovolemia, severe left ventricular outflow obstruction, or patients on treatment with antihypertensives, or if the patient develops signs and symptoms of hypotension, a reduction in the dose of Riociguat is considered.

• Bleeding: During clinical trials, bleeding occurred in 2.4% of patients taking Riociguat compared to 0% of placebo patients; five patients taking Riociguat reported hemoptysis compared to 0 placebo patients, hemorrhagic events were also reported.

For Patients

What is Pulmonary Hypertension?

Pulmonary hypertension occurs due to increased pressure in the blood vessels, which carry blood from the heart to the lungs. This increase in pressure can cause the narrowing of the arteries of the lungs resulting in reduced blood flow and oxygen. It can slowly worsen and can be a life-threatening disease. It is mainly caused by congenital heart disease, high blood pressure, liver cirrhosis, emphysema, coronary artery disease, and blood clots in the lungs. It is characterized by difficulty breathing, fatigue, dizziness, chest pain, palpitations, and ankle swelling. It can happen at all ages, including children, and the incidence increases with age. Pulmonary hypertension is not curable, but the treatment can help reduce the symptoms and improve the quality of life.

Why Is Riociguat Prescribed?

Riociguat is a prescription medicine advised to treat pulmonary arterial hypertension and also chronic thromboembolic pulmonary hypertension in adults who cannot undergo surgery or have a recurrence of high lung blood pressure levels after surgery. Riociguat helps by improving the ability to exercise and delays the worsening of symptoms, relaxes and widens the arteries, and allows easy flow of blood. A decrease in the high blood pressure in the lungs facilitates better functioning of the heart and the lungs and improves the quality of life.

What Is the Most Important Information About Riociguat?

• Riociguat can cause serious birth defects or may harm the fetus; hence it should not be taken by pregnant women; females must not become pregnant while on treatment with Riociguat.

• Females must submit negative pregnancy reports to the doctor before the initiation of the treatment, each month during treatment, and one month after discontinuation of the treatment.

• Females who might get pregnant must use two birth control methods during the treatment and one month after stopping Riociguat.

• In case of missed menstrual period, unprotected sex, or a suspected birth control method fails, the doctor must be immediately informed.

How Should Riociguat Be Used?

• Riociguat comes in tablet form and should be taken orally, with or without food, three times a day, around the same time daily, with a spacing of six to eight hours apart. If the tablet cannot be taken as a whole, it can be crushed and mixed with a small amount of water or soft food and taken immediately.

• It should be taken as advised by the doctor, and the dose should not be changed or the medicine discontinued without informing the doctor.

• Riociguat doses must not be missed; if one dose is missed, the next dose must be taken at the regular time. If three or more days of treatment are missed, the doctor must be informed before restarting the treatment.

• The treatment is started on a low dose and gradually increased, not more than once every two weeks. The dose may be decreased if any side effects are observed.

• Regular blood pressure monitoring is done every two weeks to help the doctor decide the correct dose for the patient.

• Patients must inform the doctor in case of low blood pressure symptoms when noticed, such as dizziness, lightheadedness, or fainting.

What Are the Special Precautions to Be Followed While Taking Riociguat?

• The patient must inform the doctor in case of allergy to Riociguat or any other medications.

• The doctor must be informed if the patient is taking any medications having nitrates such as isosorbide dinitrate, nitroglycerin, phosphodiesterase inhibitors such as Avanafil, Sildenafil, Tadalafil, or Dipyridamole or Theophylline. If the patient takes any or more of these drugs, the doctor may advise not to take Riociguat. Riociguat should not be taken 24 hours before or after taking Sildenafil or within 24 hours before and 48 hours after taking Tadalafil.

• The doctor must be informed if the patient is under any other medications, vitamin or nutritional supplements, herbal products, anti-fungal medicines such as Itraconazole, Ketoconazole, seizure medications such as Carbamazepine, Phenobarbital, Phenytoin, or blood pressure medications. The doctor may change the doses or may monitor for any side effects.

• Antacids containing aluminum hydroxide or magnesium hydroxide must be taken one hour before or after taking Riociguat.

• The doctor must be informed in case of smoking, as smoking needs to be stopped during the treatment.

• The patient must inform in the case of recent diarrhea, vomiting, or sweating leading to dehydration (loss of large amounts of body fluids).

• Patients must also inform in case of low blood pressure, pulmonary veno-occlusive disease (a block in the veins), or in case of heart, liver, or kidney diseases.

• The doctor must be informed about breastfeeding before initiating treatment, and while treating with Riociguat, breastfeeding should not be done.

• Riociguat can cause dizziness and lightheadedness, so driving must be avoided until the side effects of the medication are understood.

• Riociguat must not be used for a condition for which it is not prescribed. It should not be given to others even if they have the same symptoms, as it may cause harm.

Who Should Not Take Riociguat?

• Pregnant women must not take Riociguat as it may harm the fetus, and females must not become pregnant during the course of treatment.

• Patients under treatment for heart diseases or high blood pressure with medications such as Nitroglycerin, Amyl Nitrite, etc. Patients under other medications to treat pulmonary arterial hypertension, such as Sildenafil, Tadalafil, etc.

• Riociguat must not be taken by patients with pulmonary hypertension associated with idiopathic interstitial pneumonia.

What Special Dietary Instructions Need to Be Followed While Taking Riociguat?

Unless the doctor advises any instructions about the diet, a normal diet can be followed during the treatment with Riociguat.

What Are the Side Effects of Riociguat?

Riociguat may cause certain side effects. The patient must inform the doctor if any of the following symptoms are observed:

• Headache.

• Constipation.

• Heartburn.

• Stomach upset.

• Nausea.

• Vomiting.

• Diarrhea.

• Swelling of hands, feet, and ankles.

Some side effects can be severe, and the doctor must be contacted immediately if these side effects are observed:

• Symptoms of reduced blood pressure such as dizziness, lightheadedness, fainting, etc.

• Coughing up pink, frothy sputum or blood.

• Fainting.

• Chest pain.

• Shortness of breath.

What Are the Precautions to Be Taken for the Storage of Riociguat?

Riociguat must be kept in the container it came in and must be tightly closed and out of reach from children. It must be stored at room temperature (between 15 to 30 Degrees Celsius) and kept away from excess heat and moisture. Medicines must be kept out of reach and sight of children as many containers may not be child-resistant, and children can open them easily. Medicines must be kept in a safe location, with safety caps locked to prevent young children from poisoning.

What Are the Precautions to Be Taken for the Disposal of Riociguat?

Medicines that are not needed should be disposed of so that pets, children, or other people cannot consume them. It should not be flushed in the toilet. The best way of disposal is through a medicine take-back program. A pharmacist or garbage recycling department can be contacted to learn about the take-back programs in the community.

What Should Be Done in Case of an Overdose?

In case of an overdose, the poison control helpline must be contacted immediately; if the patient has collapsed or in case of seizures, trouble breathing, or cannot be awakened, emergency services are immediately contacted.

Other Information:

All the appointments with the doctor are noted, and blood pressure is checked regularly during the treatment with Riociguat. Nobody else other than the patient must take the medication. A written list of all the prescribed and over-the-counter drugs, vitamins, minerals, or dietary supplements taken during the course of treatment must be maintained and brought each time the patient has an appointment or is admitted to a hospital or in case of emergency.

For Doctors

Mechanism of Action:

In healthy humans, nitric oxide (NO) is produced by the endothelium in blood vessels, the airway, and epithelial cells in alveoli, which get dispersed into the layer of smooth muscle cells. There they act by binding to the heme group over the enzyme soluble guanylate cyclase (sGC) that catalyzes the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP). The cGMP acts through various protein kinases, reduces intracellular calcium concentration, and inhibits the contraction of smooth muscles. A decrease in NO production has been noted associated with PAH, CTEPH, lung diseases, and chronic obstructive pulmonary disease (COPD). Riociguat acts through a dual mechanism; by indirectly activating NO by sensitizing the binding of sGC with the available NO generated endogenously. The other mechanism is by directly activating sGC without the need for the stimulus of NO.

Drug Interactions:

• Pharmacodynamic Interactions With Riociguat:

• Riociguat must be discontinued at least 24 hours before the administration of the PDE5 inhibitor, along with monitoring the signs and symptoms of hypotension.

• Co-administration of Riociguat with nitrates and nitric oxide donors in any form is contraindicated, as it can lead to hypotension.

• Co-administration of Riociguat with specific PDE-5 inhibitors and non-specific PDE inhibitors is contraindicated as it can cause hypotension. Specific PDE-5 inhibitors such as Sildenafil must be discontinued at least 24 hours before the administration of Riociguat. Tadalafil must be discontinued at least 48 hours before the administration of Riociguat, and initiation of a starting dose of 0.5 mg in patients at risk of hypotension, along with monitoring signs and symptoms of hypotension.

• Pharmacokinetic Interactions With Riociguat:

• Plasma concentration in smokers is reduced by 50 to 60% compared to nonsmokers, doses higher than 2.5 mg three times a day may be done, and dose reduction followed by discontinuation of smoking.

• Concomitant use of strong cytochrome inhibitors such as azole antimycotics and use of HIV protease inhibitors with Riociguat may cause increased exposure to Riociguat resulting in hypotension. An initial dose of 0.5 mg three times a day is considered, along with cytochrome inhibitors, followed by regular monitoring for signs and symptoms of hypotension, and dose reduction is considered in patients who cannot tolerate the hypotensive effect of Riociguat.

• Medications like Rifampicin, Phenytoin, Carbamazepine, and Phenobarbital may decrease Riociguat exposure; hence co administration should be avoided.

• Antacids may decrease Riociguat absorption, so they should not be taken within one hour of taking Riociguat.

Adverse Reactions of Riociguat:

• Embryo-Fetal Toxicity: Riociguat, when administered in pregnant women, may harm the fetus; consistent teratogenic effects were reported when Riociguat was administered in animals; hence, it is contraindicated in pregnant women.

• Hypotension: Riociguat reduces blood pressure, but it may cause symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular obstruction, autonomic dysfunction, and concomitant treatment with antihypertensives.

• Bleeding: During placebo-controlled clinical trials, serious bleeding occurred in patients taking Riociguat compared to placebo patients. Hemoptysis was reported in five patients taking Riociguat, compared to 0 in placebo patients, including one fatal outcome. Serious hemorrhagic events were reported in two patients with vaginal hemorrhage, two patients with catheter site hemorrhage, and one patient each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage.

Clinical Studies of Riociguat:

Phase I and II Studies for Use in Both PAH and CTEPH:

• Initial study on 58 healthy volunteers, administered Riociguat 1 mg and 5 mg significantly reduced the mean arterial blood pressure.

• In the following proof of concept trial,19 patients were administered Riociguat 1mg/2.5mg, which led to a significant dose-dependent reduction in mean pulmonary arterial pressure and increased cardiac output, leading to a marked decrease in peripheral vascular resistance.

• A 12-week open-label, uncontrolled multicentre study (phase II) conducted on 33 patients of PAH and 42 patients of CTEPH receiving baseline therapy with Bosentan, followed by 1 to 2.5 mg of Riociguat, demonstrated its overall well tolerability. The most common adverse effects reported were headache, dyspepsia, and hypotension, considered mild to moderate in 96% of cases, with only four percent of participants discontinuing Riociguat.

• Phase II double-blind, randomized, the placebo-controlled study recruited 18 patients of PAH and started with Sildenafil therapy followed by randomization to receive either Riociguat or placebo after 12 weeks, and follow-up was done for around 305 days. Almost 53% reported serious adverse events; three patients died in due course but were not attributed to Riociguat. Due to this unfavorable result, a combination of a Riociguat and phosphodiesterase inhibitor is not used.

• Phase III Studies:

• PATENT - 1: A 12-week randomized, double-blind, placebo-controlled study recruited 443 patients of symptomatic PAH and demonstrated improvement in walking distance time in the group taking 2.5 mg Riociguat compared to placebo. Riociguat was approved for use in PAH to improve exercise capacity.

• PATENT - 2: This was an open-label extension of those recruited in the PATENT - 1 study, in which 396 individuals participated. Although efficacy parameters were maintained even at two years, 59% of patients developed adverse effects related to the drug, with 13 cases of hemoptysis and pulmonary hemorrhages with two fatalities.

• CHEST-1: A 16-week, randomized, double-blind, placebo-controlled study recruited 261 cases of inoperable CTEPH, persistent or recurrent pulmonary hypertension demonstrated improvement in walking compared to placebo.

• CHEST-2: Open-label extension of CHEST-1 study demonstrated sustained improvement in walking distance at two years, with 2.5 mg of Riociguat

Nonclinical Toxicity:

Studies in rats and mice have not demonstrated any evidence of carcinogenesis, even after administering doses six to seven times higher than the human equivalent dose. No evidence of mutation in assays using Chinese Hamster V79 cells. Fertility was not impaired in male or female rats even after administering doses 37 times that of the human dose.

Use of Riociguat in Specific Populations:

• Pregnancy: Riociguat was found to be teratogenic and embryotoxic in rats at doses with exposure to the unbound drug approximately eight times and two times the human exposure. In rabbits, Riociguat led to abortions at four times the human exposure and fetal toxicity 13 times the human exposure. Riociguat may cause fetal harm when administered to a pregnant woman and is contraindicated in pregnancy.

• Nursing: Riociguat or its metabolites were present in the milk of rats; it is not known if Riociguat is present in human milk. Many drugs are present in human milk, which may cause potential hazards in infants; hence, breastfeeding or Riociguat is discontinued.

• Pediatric Use: The safety and effectiveness of Riociguat have not been established in pediatric patients.

• Geriatric Use: No overall differences were observed regarding the safety and effectiveness of using Riociguat in geriatric patients and younger patients, but sensitivity in geriatric patients compared to younger patients cannot be ruled out.

• Gender: Females are advised to take Riociguat only under the REMS program and have negative pregnancy reports during the course of treatment, whereas male patients are not enrolled in the REMS program.

• Renal and Hepatic Impairment: Safety and efficacy have not been demonstrated in patients with renal or severe hepatic impairment.