Consumer medicine information

Verquvo

Vericiguat

BRAND INFORMATION

Brand name

Verquvo

Active ingredient

Vericiguat

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Verquvo.

SUMMARY CMI

VERQUVO®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new. Please report side effects. See the full CMI for further details.

1. Why am I using VERQUVO®?

VERQUVO® contains the active ingredient vericiguat. VERQUVO® is used to treat heart failure.

For more information, see Section 1. Why am I using VERQUVO®? in the full CMI.

2. What should I know before I use VERQUVO®?

Do not use if you have ever had an allergic reaction to vericiguat or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use VERQUVO®? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with VERQUVO® and affect how it works. Do not take VERQUVO® if you are taking riociguat, or medicine for erectile dysfunction.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use VERQUVO®?

Take one (1) tablet of VERQUVO® at the same time each day with food. The usual recommended target dose of VERQUVO® is 10mg once a day. You will usually start by taking 2.5mg tablet once a day for the first 2 weeks.

More instructions can be found in Section 4. How do I use VERQUVO®? in the full CMI.

5. What should I know while using VERQUVO®?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using VERQUVO®.
  • Call your doctor if you feel dizzy, lightheaded, or develop signs or symptoms of an allergic reaction.
Things you should not do
  • Do not take VERQUVO® to treat any other complaints unless your doctor tells you to.
  • Do not stop taking your medicine or lower the dose without checking with your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how VERQUVO® affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • The effects of VERQUVO® with alcohol are unknown.
Looking after your medicine
  • Store below 30°C. Store it in a cool dry place away from moisture, heat or sunlight.
  • Keep it where young children cannot reach it.

For more information, see Section 5. What should I know while using VERQUVO®? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. You may experience side effects while taking VERQUVO®, most of them are minor and temporary. You should call your doctor if you become dizzy or lightheaded, this may be a sign of low blood pressure.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

VERQUVO® (ver-KYU-voh)

Active ingredient(s): vericiguat

Consumer Medicine Information (CMI)

This leaflet provides important information about using VERQUVO®. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using VERQUVO®.

Where to find information in this leaflet:

1. Why am I using VERQUVO®?
2. What should I know before I use VERQUVO®?
3. What if I am taking other medicines?
4. How do I use VERQUVO®?
5. What should I know while using VERQUVO®?
6. Are there any side effects?
7. Product details

1. Why am I using VERQUVO®?

VERQUVO® contains the active ingredient vericiguat. It is a heart therapy medicine, called a soluble guanylate cyclase stimulator.

Your doctor would have prescribed this medicine because you may have had an increase or worsening of your heart failure symptoms recently.

Heart failure is when your heart is weak and can't pump enough blood to your body. Common symptoms of heart failure may include difficulty breathing, swelling and fatigue.

VERQUVO® works by widening the arteries to make it easier for the heart to get more blood and oxygen throughout the body. VERQUVO® can lower your chances of having to go hospital for your heart failure.

VERQUVO® is used along with other heart failure medicines.

2. What should I know before I use VERQUVO®?

Warnings

Do not use VERQUVO® if:

  • you are taking another soluble guanylate cyclase stimulator, such as ADEMPAS® (riociguat) used to treat high blood pressure in the lungs.
  • you are allergic to vericiguat or any of the other ingredients in this medicine listed under Section 7 Product details.

If any of the above applies to you, talk to your doctor first and do not take VERQUVO®.

Check with your doctor if you:

  • have low blood pressure.
  • have liver problems.
  • have kidney problems or are on dialysis.
  • take any medicines for any other condition.

During treatment, you may experience some side effects. It is important you understand what these may be and how to monitor for them. See additional information under Section 6. Are there any side effects?

VERQUVO® contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking it.

Pregnancy and breastfeeding

VERQUVO® is not recommended during pregnancy, as it is not known if it will harm your unborn baby. Use an effective contraception to prevent pregnancy while on VERQUVO®. Talk to your doctor if you are pregnant or intend to become pregnant.

Breastfeeding is not recommended while taking VERQUVO®. It is not known whether it passes into your breast milk and may harm your baby. Tell your doctor if you are breast-feeding or about to start breast-feeding before taking this medicine.

Children and adolescents

Do not give VERQUVO® to children and adolescents under 18 years. VERQUVO® has not been studied in this age group.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Do not take VERQUVO® if:

  • you are taking another soluble guanylate cyclase stimulator, such as ADEMPAS® (riociguat) used to treat high blood pressure in the lungs.
  • you take medicine for erectile dysfunction (e.g. sildenafil, tadalafil, vardenafil).

Tell your doctor if you are taking medicines for angina (chest pain) called nitrates (e.g. glyceryl trinitrate, isosorbide mononitrate).

Know the medicines you take. Keep a list of them to show to your doctor or pharmacist when you get a new medicine.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect VERQUVO®.

4. How do I use VERQUVO®?

How much to take

Follow all directions given to you by your doctor and pharmacist carefully. They may be different to what is in this leaflet.

Take one (1) tablet of VERQUVO® at the same time each day with food.

The usual recommended target dose of VERQUVO® is 10mg once a day. You will usually start by taking 2.5mg tablet once a day for the first 2 weeks. Your doctor will gradually increase your dose every 2 weeks, depending on how you respond.

Follow the instructions provided and use VERQUVO® until your doctor tells you to stop. Do not stop taking VERQUVO® or change your dose without talking to your doctor.

If you are not able to swallow tablets, VERQUVO® may be crushed and mixed with water immediately before taking.

When to take VERQUVO®

Take VERQUVO® at the same time each day with food.

If you forget to take VERQUVO®

VERQUVO® should be taken regularly at the same time each day. If you miss your dose at the usual time, take the missed dose as soon as you remember only on the same day of the missed dose. If you remember the next day, then skip the dose you missed and take your next dose when you are meant to.

Do not take two doses of VERQUVO® on the same day.

If you are not sure how to take VERQUVO®, call your doctor or pharmacist.

If you use too much VERQUVO®

If you think that you have used too much VERQUVO®, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using VERQUVO®?

Things you should do

Take VERQUVO® exactly as directed by your doctor.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking VERQUVO®.

Call your doctor straight away if you:

  • feel dizzy or lightheaded.
  • develop signs or symptoms of an allergic reaction, including: shortness of breath; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.
  • notice any side effects that may be making you feel unwell.
  • think that you have used too much VERQUVO®.

Things you should not do

  • Do not take VERQUVO® to treat any other complaints unless your doctor tells you to.
  • Do not stop taking your medicine or lower the dose without checking with your doctor.
  • Do not give your medicine to anyone else, even if they have the same condition as you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how VERQUVO® affects you.

VERQUVO® can cause dizziness. Do not drive or use machinery if you feel dizzy while using VERQUVO®.

Drinking alcohol

Tell your doctor if you drink alcohol.

The effects of VERQUVO® with alcohol are unknown.

Looking after your medicine

  • Store below 30°C.

Follow the instructions on the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Blood and lymphatic system disorders:
  • Low number red blood cells (anemia) seen as pale skin, weakness or breathlessness.
Gastrointestinal disorders:
  • Feeling like you are going to throw up (nausea).
  • Vomiting.
  • Indigestion (dyspepsia).
  • Heartburn (gastroesophageal reflux disease).
Nervous system disorders:
  • Dizziness.
  • Headache.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Vascular disorders:
  • Low blood pressure (hypotension).
Call your doctor if you become dizzy or lightheaded.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell. Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What VERQUVO® contains

Active ingredient
(main ingredient)		Vericiguat
Other ingredients
(inactive ingredients)		Tablet core
Microcrystalline cellulose
Croscarmellose sodium
Hypromellose 5 cP
Lactose monohydrate
Magnesium stearate
Sodium lauryl sulfate
Film-coat
Hypromellose 5 cP
Purified talc
Titanium dioxide (E 171)
Iron oxide red (E 172) (VERQUVO® 5 mg only)
Iron oxide yellow (E 172) (VERQUVO® 10 mg only)

Do not take this medicine if you are allergic to any of these ingredients.

What VERQUVO® looks like

VERQUVO® 2.5 mg film-coated tablets are round, biconvex, white film-coated tablet with a diameter of 7 mm, debossed with “2.5” on one side and “VC” on the other side (AUST R 339992).

VERQUVO® 5 mg film-coated tablets are round, biconvex, brown-red film-coated tablet with a diameter of 7 mm, debossed with “5” on one side and “VC” on the other side (AUST R 339994).

VERQUVO® 10 mg film-coated tablets are round, biconvex, yellow-orange film-coated tablet with a diameter of 9 mm, debossed with “10” on one side and “VC” on the other side (AUST R 339993).

VERQUVO® is available in:

  • blisters in cartons of 14 or 28 film-coated tablets.
  • perforated unit dose blisters in cartons of 100 x 1 film-coated tablets (for hospital dispensing only).

Who distributes VERQUVO®

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073
www.bayer.com.au

This leaflet was prepared in November 2021.

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

® Registered trademark

Published by MIMS December 2022

BRAND INFORMATION

Brand name

Verquvo

Active ingredient

Vericiguat

Schedule

S4

 

1 Name of Medicine

Vericiguat.

2 Qualitative and Quantitative Composition

Verquvo 2.5 mg film-coated tablets.

Each film-coated tablet contains 2.5 mg vericiguat.

Verquvo 5 mg film-coated tablets.

Each film-coated tablet contains 5 mg vericiguat.

Verquvo 10 mg film-coated tablets.

Each film-coated tablet contains 10 mg vericiguat.

Excipient with known effect.

Each 2.5 mg film-coated tablet contains 58.14 mg lactose (as monohydrate).
Each 5 mg film-coated tablet contains 55.59 mg lactose (as monohydrate).
Each 10 mg film-coated tablet contains 111.15 mg lactose (as monohydrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablets.

Verquvo 2.5 mg film-coated tablets.

Round, biconvex, white film-coated tablet with a diameter of 7 mm, debossed with "2.5" on one side and "VC" on the other side.

Verquvo 5 mg film-coated tablets.

Round, biconvex, brown-red film-coated tablet with a diameter of 7 mm, debossed with "5" on one side and "VC" on the other side.

Verquvo 10 mg film-coated tablets.

Round, biconvex, yellow-orange film-coated tablet with a diameter of 9 mm, debossed with "10" on one side and "VC" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Verquvo is indicated in addition to standard of care therapy for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction less than 45% who are stabilised after a recent heart failure decompensation event requiring admission and/or IV diuretic therapy (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Adults.

Verquvo should be initiated under the supervision of a cardiologist. The recommended starting dose of Verquvo is 2.5 mg once daily. The dose should be doubled approximately every 2 weeks to reach the target maintenance dose of 10 mg once daily, as tolerated by the patient.
Before starting Verquvo, care should be taken to optimise volume status and diuretic therapy to stabilise patients after the decompensation event, particularly in patients with very high NT-proBNP levels (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
If patients experience symptomatic hypotension, dose adjustment of concomitant diuretics and treatment of other causes of hypotension (e.g. hypovolaemia) should be considered. If symptomatic hypotension persists despite such measures, temporary reduction in dose or interruption of Verquvo should be considered (see Section 4.4 Special Warnings and Precautions for Use).
Treatment should not be initiated in patients with SBP < 100 mmHg (see Section 4.4 Special Warnings and Precautions for Use).

Method of administration.

For oral use. Verquvo should be taken with food (see Section 5.2 Pharmacokinetic properties).
For patients who are unable to swallow whole tablets, Verquvo may be crushed and mixed with water immediately before administration (see Section 5.2 Pharmacokinetic Properties).

Missed dose.

If a dose is missed, it should be taken as soon as the patient remembers on the same day of the missed dose. Patients should not take two doses of Verquvo on the same day.

Renal impairment.

No dose adjustment of Verquvo is required in patients with estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2 (without dialysis). Verquvo has not been studied in patients with eGFR < 15 mL/min/1.73 m2 at treatment initiation or on dialysis and is therefore not recommended in these patients (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment; Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties, Special populations).

Hepatic impairment.

No dose adjustment of Verquvo is required in patients with mild or moderate hepatic impairment. Verquvo has not been studied in patients with severe hepatic impairment and is therefore not recommended in these patients (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment; Section 5.2 Pharmacokinetic Properties, Special populations).

Geriatric patients.

No dosage adjustment of Verquvo is required for geriatric patients (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly; Section 5.2 Pharmacokinetic Properties, Special populations).

Paediatric patients.

Safety and efficacy of Verquvo have not been established in patients less than 18 years of age (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use; Section 5.2 Pharmacokinetic Properties, Special populations).

4.3 Contraindications

Verquvo is contraindicated in patients with:
hypersensitivity to the active substance or any of the excipients listed in Section 6.1 List of Excipients;
concomitant use of other soluble guanylate cyclase (sGC) stimulators, such as riociguat (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Symptomatic hypotension.

Verquvo may cause symptomatic hypotension. In the VICTORIA clinical trial, adverse events determined by the investigator to be events of symptomatic hypotension were reported in 9.1% of patients treated with vericiguat and 7.9% of patients treated with placebo and were considered serious in 1.2% of patients treated with vericiguat and 1.5% of patients treated with placebo (see Section 4.8 Adverse Effects (Undesirable Effects)). Verquvo has not been studied in patients with systolic blood pressure less than 100 mmHg or symptomatic hypotension at treatment initiation.
Consider the potential for symptomatic hypotension in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, history of hypotension, or concomitant treatment with antihypertensives or organic nitrates (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If symptomatic hypotension occurs, consider dose adjustment of diuretics and treatment of other causes of hypotension (e.g. hypovolemia). If symptomatic hypotension persists despite such measures, temporary reduction in dose or interruption of Verquvo should be considered.
Concomitant use of Verquvo and phosphodiesterase-5 (PDE-5) inhibitors, such as sildenafil, has not been studied in patients with heart failure and is therefore not recommended due to the potential increased risk for symptomatic hypotension (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in renal impairment.

No dose adjustment of Verquvo is required in patients with eGFR ≥ 15 mL/min/1.73 m2 (without dialysis). Verquvo has not been studied in patients with eGFR < 15 mL/min/1.73 m2 at treatment initiation or on dialysis and is therefore not recommended in these patients (see Section 4.2 Dose and Method of Administration, Renal impairment; Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties, Special populations).

Use in hepatic impairment.

No dose adjustment of Verquvo is required in patients with mild or moderate hepatic impairment. Verquvo has not been studied in patients with severe hepatic impairment and is therefore not recommended in these patients (see Section 4.2 Dose and Method of Administration, Hepatic impairment; Section 5.2 Pharmacokinetic Properties, Special populations).

Use in the elderly.

No dosage adjustment of Verquvo is required in geriatric patients. In VICTORIA, a total of 1,596 (63%) patients treated with Verquvo were 65 years and older and 783 (31%) patients treated with Verquvo were 75 years and older. No overall differences in safety or efficacy of Verquvo were observed between patients aged 65 years and older compared to younger patients, but greater sensitivity of some older individuals cannot be ruled out (see Section 4.2 Dose and Method of Administration, Geriatric patients; Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties, Special populations).

Paediatric use.

Safety and efficacy of Verquvo have not been established in patients less than 18 years of age (see Section 4.2 Dose and Method of Administration, Paediatric patients; Section 5.2 Pharmacokinetic Properties, Special populations). Undesirable effects were observed on growing bone in non-clinical studies (see Section 5.3 Preclinical Safety Data, Toxicity).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Contraindications of concomitant use.

Other soluble guanylate cyclase (sGC) stimulators.

Verquvo is contraindicated in patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators, such as riociguat (see Section 4.3 Contraindications).

Concomitant use not recommended.

PDE5 inhibitors.

Addition of single doses of sildenafil (25, 50, or 100 mg) to multiple doses of vericiguat (10 mg) once daily in healthy subjects was associated with additional seated blood pressure (BP) reduction of less than or equal to 5.4 mmHg (systolic/diastolic BP, mean arterial pressure [MAP]) compared to administration of vericiguat alone. No dose-dependent trend was observed with the different sildenafil doses.
Co-administration was not associated with a clinically relevant effect on the exposure (AUC and Cmax) of either medicinal product.
Concomitant use of Verquvo and PDE5 inhibitors, such as sildenafil, has not been studied in patients with heart failure and is therefore not recommended due to the potential increased risk for symptomatic hypotension (see Section 4.4 Special Warnings and Precautions for Use, Symptomatic hypotension).

Other interactions.

Combination of sacubitril/valsartan.

Addition of multiple doses of vericiguat (2.5 mg) to multiple doses of sacubitril/valsartan (97/103 mg) in healthy subjects had no additional effect on seated blood pressure compared to administration of sacubitril/valsartan alone.
Co-administration was not associated with a clinically relevant effect on the exposure (AUC and Cmax) of either medicinal product.

Concomitant use with drugs that increase gastric pH.

Co-treatment with medicinal products that increase gastric pH, such as proton pump inhibitors (omeprazole), H2 receptor antagonists or antacids (aluminium hydroxide/magnesium hydroxide) did not affect vericiguat exposure when vericiguat was taken as directed with food in heart failure patients (see Section 4.2 Dose and Method of Administration).

Acetylsalicylic acid.

Administration of a single dose of vericiguat (15 mg) in healthy subjects did not alter the effect of acetylsalicylic acid (500 mg) on bleeding time or platelet aggregation. Bleeding time or platelet aggregation did not change under treatment with vericiguat (15 mg) alone.
Co-administration of acetylsalicylic acid was not associated with a clinically relevant effect on the exposure (AUC and Cmax) of vericiguat.

Warfarin.

Administration of multiple doses of vericiguat (10 mg) once daily in healthy subjects did not alter the effect of a single dose of warfarin (25 mg) on prothrombin time and the activities of Factors II, VII, and X.
Co-administration was not associated with a clinically relevant effect on the exposure (AUC and Cmax) of either medicinal product.

Organic nitrates.

Co-administration of multiple doses of vericiguat increased to 10 mg once daily did not significantly alter the seated blood pressure effects of short and long-acting nitrates (nitroglycerin spray and isosorbide mononitrate [ISMN]) in patients with coronary artery disease. In patients with heart failure, concomitant use of short-acting nitrates was well tolerated. There is limited experience with concomitant use of vericiguat and long-acting nitrates in patients with heart failure (see Section 4.4 Special Warnings and Precautions for Use, Symptomatic hypotension).

No significant interactions.

No clinically meaningful effect on midazolam (CYP3A substrate) or digoxin (P-gp substrate) exposure was observed when vericiguat was co-administered with these medicinal products.
No clinically meaningful effect on vericiguat exposure was observed when vericiguat was coadministered with ketoconazole (multi pathway CYP and transporter inhibitor), mefenamic acid (UGT1A9 inhibitor), rifampicin (multi pathway UGT, CYP and transporter inducer), or digoxin.
No clinically meaningful effect on vericiguat exposure was predicted when vericiguat is coadministered with atazanavir (UGT1A1 inhibitor), based on physiologically based PK (PBPK) modelling.

In vitro assessment of drug interactions.

In vitro studies indicate that vericiguat and its N-glucuronide are neither inhibitors of major CYP isoforms (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) or UGT isoforms (UGT1A1, 1A4, 1A6, 1A9, 2B4, and 2B7), nor inducers of CYP1A2, 2B6 and 3A4, at clinically relevant concentrations.
Vericiguat is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters and is not a substrate of organic cation transporter (OCT1) or organic anion transporting polypeptides (OATP1B1, OATP1B3). Vericiguat and its N-glucuronide are not inhibitors of drug transporters, including P-gp, BCRP, BSEP, OATP1B1/1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2K, at clinically relevant concentrations.
Overall, these data indicate that the administration of vericiguat is unlikely to affect the pharmacokinetics of concurrently administered medications that are substrates of these enzymes or transporters.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data available on the effect of vericiguat on human fertility. In a fertility and early embryonic development study in male and female rats, vericiguat when administered orally at doses of 5, 15 or 50 mg/kg/day had no effects on fertility or reproductive performance at up to the highest dose tested of 50 mg/kg/day (64 times the human exposure at the maximum recommended human dose (MRHD) of 10 mg/day, unbound AUC).
(Category D)
There are no data from the use of vericiguat in pregnant women. Verquvo should not be used in pregnancy. Women of childbearing potential should use effective forms of contraception during treatment.
A study in pregnant rats showed that vericiguat is transferred to the fetus through the placenta. Development toxicity studies in rats with vericiguat administered orally during organogenesis showed no development toxicity up to 50 mg/kg/day (75 times the human unbound AUC at the MRHD of 10 mg). Exaggerated pharmacodynamic-mediated maternal toxicity was observed ≥ 21 times the human unbound AUC at the MRHD; there was no maternal toxicity at 9 times the human exposure at MRHD.
In rabbits, the exaggerated pharmacodynamic-mediated maternal toxicity was observed at 2.5 mg/kg/day and above (≥ 6 times the human unbound AUC at the MRHD) resulting in secondary late spontaneous abortions and resorptions. In addition, at this dose, a low incidence of malformation of the heart and major vessels was seen. While this could not be unambiguously attributed to vericiguat treatment, cardiac and major vessel abnormalities were observed following maternal administration of a structurally related compound (riociguat) to rats. No maternal, embryofetal or development toxicity was seen in rabbits following maternal oral doses of 0.75 mg/kg/day (approximately equivalent to the human exposure, based on unbound AUC, at the MRHD).
In a pre/postnatal toxicity study, vericiguat administered orally to rats during gestation through lactation showed exaggerated pharmacodynamic-mediated maternal toxicity at approximately ≥ 9 times the human exposure at the MRHD, which resulted in decreased pup body weight gain (≥ 21 times the MRHD) and pup mortality (45 times the MRHD) during the preweaning period.
 There is no information regarding the presence of vericiguat in human milk, the effects on the breastfed infant, or the effects on milk production. Vericiguat is present in the milk of lactating rats. A risk to the breastfed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue or abstain from Verquvo therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

Verquvo has minor influence on the ability to drive or use machines. When driving vehicles or operating machines it should be taken into account that occasionally dizziness may occur.

4.8 Adverse Effects (Undesirable Effects)

Vericiguat was evaluated in VICTORIA, a Phase 3 randomised, placebo-controlled, double-blind, clinical trial in adult patients with symptomatic chronic heart failure and ejection fraction less than 45% following a worsening heart failure event, which included a total of 2,519 patients treated with vericiguat (up to 10 mg once daily) and 2,515 patients treated with matching placebo (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The mean duration of vericiguat exposure was 1 year, and the maximum duration was 2.6 years. Table 1 lists adverse drug reactions occurring in patients treated with vericiguat and greater than placebo in VICTORIA. Table 2 lists the frequency of adverse reactions occurring in patients treated with vericiguat in VICTORIA by MedDRA System Organ Class. 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), and very rare (< 1/10,000).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Limited data are available with regard to overdosage in human patients treated with Verquvo. In VICTORIA, doses up to 10 mg were studied. In a study of patients with preserved ejection fraction heart failure (left ventricular ejection fraction ≥ 45%), multiple doses of vericiguat (15 mg) were studied and were generally well tolerated. In the event of an overdose, hypotension may result. If necessary, symptomatic treatment should be provided. Verquvo is unlikely to be removed by haemodialysis due to high protein binding.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Therapeutic class.

Soluble guanylate cyclase (sGC) stimulator.
Pharmacotherapeutic group: Cardiac therapy, ATC code: C01DX22 vericiguat.

Mechanism of action.

Vericiguat is a stimulator of soluble guanylate cyclase (sGC). Heart failure is associated with impaired synthesis of nitric oxide (NO) and decreased activity of its receptor, sGC. Soluble guanylate cyclase catalyses synthesis of intracellular cyclic guanosine monophosphate (cGMP), an important signalling molecule that regulates critical physiological processes such as cardiac contractility, vascular tone, and cardiac remodelling. Deficiency in sGC-derived cGMP contributes to myocardial and vascular dysfunction. Vericiguat restores the relative deficiency in this signalling pathway by directly stimulating sGC, independently of and synergistically with NO, to augment the levels of intracellular cGMP, which may improve both myocardial and vascular function. The complementary cardiovascular benefits of vericiguat in heart failure patients are therefore attributed to the active restoration of the deficient NO-sGC-cGMP pathway driving heart failure progression.

Pharmacodynamic effects.

The pharmacodynamic effects of vericiguat were evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure and are consistent with the mode of action of an sGC stimulator resulting in smooth muscle relaxation and vasodilation. Over the course of the VICTORIA study, the mean reduction in systolic blood pressure was approximately 1 to 2 mmHg greater in patients who received vericiguat compared with placebo.
In a 12-week placebo-controlled dose-finding study (SOCRATES-REDUCED) in patients with heart failure, vericiguat demonstrated a dose-dependent reduction in NT-proBNP, a biomarker in heart failure, compared to placebo when added to standard of care. In VICTORIA, the estimated reduction from baseline NT-proBNP at week 32 was greater in patients who received vericiguat compared with placebo (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Cardiac electrophysiology.

In a dedicated QT study in patients with stable coronary artery disease, administration of vericiguat 10 mg at steady-state did not prolong the QT interval to a clinically relevant extent, i.e. the maximum mean prolongation of the QTcF interval did not exceed 6 ms (upper bound of the 90%CI < 10 ms).

Clinical trials.

The safety and efficacy of vericiguat were evaluated in a randomised, parallel-group, placebo-controlled, double-blind, event-driven, multi-centre trial (VICTORIA) comparing vericiguat and placebo in 5,050 adult patients with symptomatic chronic heart failure (NYHA class II-IV) and left ventricular ejection fraction (LVEF) less than 45% following a worsening heart failure event. A worsening chronic heart failure event was defined as heart failure hospitalisation within 6 months before randomisation or use of outpatient IV diuretics for heart failure within 3 months before randomisation.
Patients were treated up to the target maintenance dose of vericiguat 10 mg once daily or matching placebo in combination with other heart failure therapies. Therapy was initiated at 2.5 mg vericiguat once daily and increased in approximately 2 week intervals to 5 mg once daily and then 10 mg once daily, as tolerated. After approximately 1 year, 90% of patients in both the vericiguat and placebo arms were treated with the 10 mg target dose.
The primary endpoint was the time to first event of the composite of cardiovascular (CV) death or hospitalisation for heart failure (HF). The median follow up for the primary endpoint was 11 months. Patients on vericiguat were treated for a mean duration of 1 year and up to 2.6 years.
The mean age of the studied population was 67 years, a total of 1,596 (63%) patients treated with vericiguat were 65 years and older, and 783 (31%) patients treated with vericiguat were 75 years and older. At randomisation, 58.9% of patients were NYHA Class II, 39.7% were NYHA Class III, and 1.3% were NYHA Class IV. The mean LVEF was 28.9%, approximately half of all patients had an LVEF < 30%, and 14.3% of patients had an LVEF between 40% and 45%. The most frequently reported medical history conditions other than heart failure included hypertension (79%), coronary artery disease (58%), hyperlipidaemia (57%), diabetes mellitus (47%), atrial fibrillation (45%), and myocardial infarction (42%). At randomisation, the mean eGFR was 62 mL/min/1.73 m2 (88% of patients > 30 mL/min/1.73 m2; 10% of patients ≤ 30 mL/min/1.73 m2). 67% of the patients in VICTORIA were enrolled within 3 months of a HF hospitalisation index event; 17% were enrolled within 3 to 6 months of HF hospitalisation and 16% were enrolled within 3 months of outpatient treatment with IV diuretics for worsening HF. The median NT proBNP level was 2,816 picogram/mL at randomisation.
At baseline, more than 99% of patients were treated with other heart failure therapies which included beta blockers (93%), angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) (73%), mineralocorticoid receptor antagonists (MRA) (70%), a combination of an angiotensin receptor and neprilysin inhibitor (ARNI) (15%), ivabradine (6%), implantable cardiac defibrillators (28%), and biventricular pacemakers (15%). 91% of patients were treated with 2 or more heart failure medications (beta blocker, any renin-angiotensin system [RAS] inhibitor, or MRA) and 60% of patients were treated with all 3. 3% of patients were on a sodium glucose co transporter 2 (SGLT2) inhibitor.
Vericiguat was superior to placebo in reducing the risk of CV death or HF hospitalisation based on a time to event analysis (hazard ratio [HR]: 0.90, 95% confidence interval [CI], 0.82 0.98; p=0.019). Over the course of the study, the annualised absolute risk reduction (ARR) was 4.2% with vericiguat compared with placebo. Therefore, 24 patients would need to be treated over an average of 1 year to prevent 1 primary endpoint event. The treatment effect reflected a reduction in both CV death and HF hospitalisation (see Table 3 and Figure 1).
Vericiguat was superior to placebo in reducing the risk of all-cause mortality or HF hospitalisation (HR 0.90 [95% CI, 0.83 0.98]) and total events (first and recurrent) of HF hospitalisation (HR 0.91 [95% CI, 0.84 0.99]) (see Table 4 and Table 5). The total number of HF hospitalisation events was greater in the placebo group (1,336 events) than in the vericiguat group (1,223 events).
A wide range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes. The results of the pre-specified subgroup analysis for the primary composite endpoint are shown in Figure 2.

5.2 Pharmacokinetic Properties

General introduction.

Vericiguat shows slightly less than dose proportional, time-independent pharmacokinetics, with low to moderate variability when administered with food. Vericiguat accumulates in plasma up to 155-171% and reaches pharmacokinetic steady-state after approximately 6 days. The mean steady-state population pharmacokinetic (PK) parameters of vericiguat in heart failure patients are summarised in Table 6.

Absorption.

The absolute bioavailability of vericiguat is high (93%) when taken with food. Bioavailability (AUC) and peak plasma levels (Cmax) of vericiguat administered orally as a crushed tablet in water is comparable to that of a whole tablet (see Section 4.2 Dose and Method of Administration).

Effect of food.

Administration of vericiguat with a high-fat, high-calorie meal increases Tmax from about 1 hour (fasted) to about 4 hours (fed), reduces PK variability, and increases vericiguat exposure by 19% (AUC) and 9% (Cmax) for the 5 mg tablet and by 44% (AUC) and 41% (Cmax) for the 10 mg tablet as compared with the fasted state. Similar results were obtained when vericiguat was administered with a low-fat, high-carbohydrate meal. Therefore, Verquvo should be taken with food (see Section 4.2 Dose and Method of Administration).

Distribution.

The mean steady-state volume of distribution of vericiguat in healthy subjects is approximately 44 L. Plasma protein binding of vericiguat is about 98%, with serum albumin being the main binding component. Plasma protein binding of vericiguat is not altered by renal or hepatic impairment.

Metabolism.

Glucuronidation is the major biotransformation pathway of vericiguat to form an N-glucuronide, which is pharmacologically inactive and the major drug related component in plasma. N-glucuronidation is catalysed predominantly by UGT1A9, as well as UGT1A1. CYP-mediated metabolism is a minor clearance pathway (< 5%).

Excretion.

Vericiguat is a low-clearance drug (1.6 L/h in healthy subjects). The half-life is about 20 hours in healthy subjects and 30 hours in heart failure patients. Following oral administration of [14C]-vericiguat to healthy subjects, approximately 53% of the dose was excreted in urine (primarily as the N-glucuronide) and 45% of the dose was excreted in faeces (primarily as vericiguat).

Special populations.

Renal impairment.

No relevant increase in exposure (AUC) was observed for heart failure patients with moderate and severe renal impairment not requiring dialysis. In patients with heart failure with moderate (eGFR ≥ 30 to < 60 mL/min/1.73 m2) and severe renal impairment (eGFR ≥ 15 to < 30 mL/min/1.73 m2) not requiring dialysis, the mean exposure (AUC) of vericiguat was increased by 13% and 20%, respectively, compared to patients with normal renal function. The pharmacokinetics of vericiguat have not been studied in patients with eGFR < 15 mL/min/1.73 m2 at treatment initiation or on dialysis (see Section 4.2 Dose and Method of Administration, Renal impairment; Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Hepatic impairment.

No relevant increase in exposure (unbound AUC) was observed for subjects with mild hepatic impairment (Child Pugh A) with mean exposure to vericiguat 21% higher compared to healthy subjects with normal hepatic function. In subjects with moderate hepatic impairment (Child Pugh B), mean exposure to vericiguat was approximately 47% higher compared to their healthy subjects with normal hepatic function. The pharmacokinetics of vericiguat have not been studied in patients with severe hepatic impairment (Child-Pugh C) (see Section 4.2 Dose and Method of Administration, Hepatic impairment; Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

Paediatric.

No studies with vericiguat have been performed in paediatric patients.

Body weight.

In a population pharmacokinetic analysis of vericiguat, the steady-state AUC values were approximately 27% higher in heart failure patients with a body weight < 60 kg and approximately 20% lower in heart failure patients with a body weight > 90 kg, compared to heart failure patients with a body weight between 60 and 90 kg. The effect of body weight on vericiguat exposure is not clinically meaningful.

Effects of age, gender, ethnicity, race, and baseline NT-proBNP.

Based on a population pharmacokinetic analysis, age, gender, ethnicity, race, and baseline NT-proBNP do not have a clinically meaningful effect on the pharmacokinetics of vericiguat.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.

Toxicity.

In rapidly-growing adolescent rats, reversible bone effects consisting of hypertrophy of growth plate and hyperostosis and remodelling of metaphyseal and diaphyseal bone were seen that were mediated by a mode of action-related intracellular cGMP increase. These effects were not observed after chronic administration of vericiguat to adult rats and almost full-grown dogs.

Genotoxicity.

Vericiguat was not genotoxic in the in vitro microbial mutagenicity (Ames) assay, the in vitro mouse lymphoma assay, and the in vivo rat and mouse micronucleus assay.

Carcinogenicity.

Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Wistar rats. Vericiguat did not show a carcinogenic effect in mice dosed in the diet at up to 150 mg/kg/day (males) or up to 250 mg/kg/day (females). These doses were associated with exposures 149 (males) or 286 (females) times the human exposure (unbound AUC) at the MRHD of 10 mg/day.
In the carcinogenicity study in rats, no vericiguat-related tumour or hyperplastic findings were seen up to exposures of 12 times the human exposure at the MRHD. A non-statistical numerical increase of benign pheochromocytomas and Leydig cell tumours as well as respective hyperplasias were observed in males after oral administration of the high dose of 20 mg/kg/day leading to exposure of 41 times the human exposure at the MRHD. This is considered a consequence of a compensatory and recurrent activation of the renin angiotensin aldosterone and the adrenergic system due to a marked daily decrease in blood pressure over 2 years. Based on the known sensitivity of rats to develop these two tumour types in contrast to humans and a documented pharmacological-based mechanism (seen also with other antihypertensive drugs) at supratherapeutic doses as well as adequate safety margins this is considered not relevant for patients.
Non-clinical data revealed no carcinogenic risk for humans at clinical doses.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Microcrystalline cellulose, croscarmellose sodium, hypromellose 5 cP, lactose monohydrate, magnesium stearate, sodium lauryl sulfate.

Film-coat.

Hypromellose 5 cP, purified talc, titanium dioxide (E 171), iron oxide red (E 172) (Verquvo 5 mg only), iron oxide yellow (E 172) (Verquvo 10 mg only).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

PVC/PVDC/Aluminium foil blisters in cartons of 14 or 28 film-coated tablets or perforated unit dose blisters in cartons of 100 x 1 film-coated tablets.
PP/Aluminium foil blisters in cartons of 14 or 28 film-coated tablets or perforated unit dose blisters in cartons of 100 x 1 film-coated tablets.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Vericiguat is a white to yellowish powder that is freely soluble in dimethyl sulfoxide, slightly soluble in acetone, very slightly soluble in ethanol, acetonitrile, methanol, ethyl acetate, and practically insoluble in 2-propanol.

Chemical name.

The chemical name of vericiguat is methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate.

Chemical structure.


The molecular formula is C19H16F2N8O2 and the molecular weight is 426.39 g/mol.

CAS number.

1350653-20-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes