What medications are used to treat PH in Canada?

Over the past 10 years, 9 new, effective medications to treat PH patients have been approved by Health Canada. Each of these medications is described individually below.

Timeline of pulmonary hypertension treatments approved in Canada:

Intravenous Flolan (Epoprostenol) : March 1997

Oral Tracleer (Bosentan) : November 2001

S/C Remodulin (Treprostinil) : October 2002

Oral Revatio (Sildenafil) : May 2006

Oral Volibris (Ambrisentan) : April 2008

Adcirca (Tadalafil) : February 2010

Caripul (RTS Epoprostenol) : September 2013

Opsumit (Macitentan) : November 2013

Adempas (Riociguat) : March 2014

Intravenous Flolan and Caripul (Epoprostenol)

Medication Trade Name	Flolan and Caripul
Medication Generic Name	Epoprostenol
Family of Medication	Prostanoids / Analogues of Prostacyclin
Form of Medication	Powder in liquid (= solution)
Route of Delivery	Intravenous = IV
Dose	Dose increases over time Initial dose 1 - 2 ng/kg/min Usual long-term dose 20 – 60 ng/kg/min
Dosing frequency	Continuous infusion 24 hours /day
Health Canada Approval Date	March, 1997
Approved for what types of PH?	WHO Group I PAH Idiopathic PAH (Primary PH = PPH) PAH associated with connective tissue disease (CTD-PAH), including scleroderma
Approved for what severity of PH?	WHO / NYHA Functional Class III and IV
Demonstrated Beneficial Effects	Improvements in pulmonary hemodynamics Reduced pulmonary artery pressure (PAP) Reduced pulmonary vascular resistance (PVR) Increased cardiac output (CO) and blood flow Improved patient function and wellbeing Reduced symptoms Improved quality of life Decreased (better) WHO / NYHA functional class level Increased exercise capacity (6-minute walk test distance) Increased patient survival In IPAH
Side Effects and Risks	Side effects Related to Medication Leg / foot pain Jaw pain Headache Diarrhea Nausea Flushing Risks Related to IV Delivery System Pain, rash, irritation at skin site where IV catheter is inserted (usually side of neck or front of upper chest) Local infection at skin site where IV catheter is inserted Blood infection Thrombosis (clotting) of the IV catheter, which may then need to be removed and a new IV catheter inserted The IV catheter may be accidentally removed or broken, so that a new IV catheter will need to be inserted Sudden interruption of Flolan treatment can quickly lead to rebound worsening of PH. Patients may experience worse symptoms of PH, as well as dizziness, low blood pressure, syncope, and risk of death.

Oral Tracleer (Bosentan)

Medication Trade Name	Tracleer
Medication Generic Name	Bosentan
Family of Medication	Endothelin Receptor Antagonists (ERAs)
Form of Medication	Tablets
Route of Delivery	Oral / by mouth
Dose	Adults Initial dose 62.5 mg for the first month Usual long-term dose 125 mg Kids Dose adjusted for weight Initial dose often 31.25 mg for the first month Usual long-term dose 62.5 mg
Dosing frequency	BID / twice daily
Health Canada Approval Date	November, 2001
Approved for what types of PH?	WHO Group I PAH Idiopathic PAH (Primary PH = PPH) PAH associated with connective tissue disease (CTD-PAH), including scleroderma PAH associated with congenital heart disease (CHD-PAH) PAH associated with HIV infection (HIV-PAH)
Approved for what severity of PH?	WHO / NYHA Functional Class III and IV
Demonstrated Beneficial Effects	Improvements in pulmonary hemodynamics Reduced pulmonary artery pressure (PAP) Reduced pulmonary vascular resistance (PVR) Increased cardiac output (CO) and blood flow Improved patient function and wellbeing Reduced symptoms Improved quality of life Decreased (better) WHO / NYHA functional class level Increased exercise capacity (6-minute walk test distance) Increased patient survival In IPAH In CTD-PAH
Side Effects and Risks	Side effects Related to Medication Edema (swelling) of legs / feet Liver toxicity Congestion of nose and sinuses Anemia (low blood hemoglobin level)

Subcutaneous Remodulin (Treprostinil)

Medication Trade Name	Remodulin
Medication Generic Name	Treprostinil
Family of Medication	Prostanoids / Analogues of Prostacyclin
Form of Medication	Powder in liquid (= solution)
Route of Delivery	Subcutaneous = SC
Dose	Dose increases over time Initial dose 2.5 ng/kg/min Usual long-term dose 30 – 100 ng/kg/min
Dosing frequency	Continuous infusion 24 hours /day
Health Canada Approval Date	October, 2002
Approved for what types of PH?	WHO Group I PAH Idiopathic PAH (Primary PH = PPH) PAH associated with connective tissue disease (CTD-PAH), including scleroderma
Approved for what severity of PH?	WHO / NYHA Functional Class III and IV
Demonstrated Beneficial Effects	Improvements in pulmonary hemodynamics Reduced pulmonary artery pressure (PAP) Reduced pulmonary vascular resistance (PVR) Increased cardiac output (CO) and blood flow Improved patient function and wellbeing Reduced symptoms Improved quality of life Decreased (better) WHO / NYHA functional class level Increased exercise capacity (6-minute walk test distance) Increased patient survival In IPAH
Side Effects and Risks	Side effects Related to Medication Leg / foot pain Jaw pain Headache Diarrhea Nausea Flushing Risks Related to SC Delivery System Pain, rash, irritation at site where subcutaneous needle is inserted and medication is delivered

Intravenous Remodulin (Treprostinil)

Medication Trade Name	Remodulin
Medication Generic Name	Treprostinil
Family of Medication	Prostanoids / Analogues of Prostacyclin
Form of Medication	Powder in liquid (= solution)
Route of Delivery	Intravenous = IV
Dose	Dose increases over time Initial dose 1 - 2 ng/kg/min Usual long-term dose 30 – 100 ng/kg/min
Dosing frequency	Continuous infusion 24 hours /day
Health Canada Approval Date	October, 2005
Approved for what types of PH?	WHO Group I PAH Idiopathic PAH (Primary PH = PPH) PAH associated with connective tissue disease (CTD-PAH), including scleroderma
Approved for what severity of PH?	WHO / NYHA Functional Class II and III
Demonstrated Beneficial Effects	It has been studied and found that IV and SC remodulin are bio-equivalent (biologically equivalent) Both IV and SC delivery systems provide the same blood levels of the medication remodulin Thus, it has been presumed that IV remodulin would also show the same beneficial effects as SC remodulin IV remodulin has also been studied in clinical trials with small numbers of patients. Improvements in pulmonary hemodynamics Reduced pulmonary artery pressure (PAP) Reduced pulmonary vascular resistance (PVR) Increased cardiac output (CO) and blood flow Improved patient function and wellbeing Reduced symptoms Improved quality of life Decreased (better) WHO / NYHA functional class level Increased exercise capacity (6-minute walk test distance)
Side Effects and Risks	Side effects Related to Medication Leg / foot pain Jaw pain Headache Diarrhea Nausea Flushing Risks Related to IV Delivery System Pain, rash, irritation at skin site where IV catheter is inserted (usually side of neck or front of upper chest) Local infection at skin site where IV catheter is inserted Blood infection Thrombosis (clotting) of the IV catheter, which may then need to be removed and a new IV catheter inserted The IV catheter may be accidentally removed or broken, so that a new IV catheter will need to be inserted

Oral Revatio (Sildenafil)

Medication Trade Name	Revatio
Medication Generic Name	Sildenafil
Family of Medication	Inhibitors of Phosphodiesterase type 5
Form of Medication	Tablets
Route of Delivery	Oral / by mouth
Dose	20 mg
Dosing frequency	TID / three times daily
Health Canada Approval Date	May, 2006
Approved for what types of PH?	WHO Group I PAH Idiopathic PAH (Primary PH = PPH) PAH associated with connective tissue disease (CTD-PAH), including scleroderma
Approved for what severity of PH?	WHO / NYHA Functional Class II and III
Demonstrated Beneficial Effects	Improvements in pulmonary hemodynamics Reduced pulmonary artery pressure (PAP) Reduced pulmonary vascular resistance (PVR) Increased cardiac output (CO) and blood flow Improved patient function and wellbeing Reduced symptoms Improved quality of life Decreased (better) WHO / NYHA functional class level Increased exercise capacity (6-minute walk test distance)
Side Effects and Risks	Side effects Related to Medication Flushing Headache Nausea Risk of Eye toxicity

Oral Volibris (Ambrisentan)

Medication Trade Name	Volibris
Medication Generic Name	Ambrisentan
Family of Medication	Endothelin Receptor Antagonists (ERAs)
Form of Medication	Tablets
Route of Delivery	Oral / by mouth
Dose	Initial dose 5 mg If inadequate response, then increase to 10 mg
Dosing frequency	once daily
Health Canada Approval Date	April, 2008
Approved for what types of PH?	WHO Group I PAH Idiopathic PAH (Primary PH = PPH) PAH associated with connective tissue disease (CTD-PAH), including scleroderma
Approved for what severity of PH?	WHO / NYHA Functional Class II and III
Demonstrated Beneficial Effects	Improvements in pulmonary hemodynamics Reduced pulmonary artery pressure (PAP) Reduced pulmonary vascular resistance (PVR) Increased cardiac output (CO) and blood flow Improved patient function and wellbeing Reduced symptoms Improved quality of life Decreased (better) WHO / NYHA functional class level Increased exercise capacity (6-minute walk test distance)
Side Effects and Risks	Side effects Related to Medication Edema (swelling) of legs / feet Liver toxicity Congestion of nose and sinuses Anemia (low blood hemoglobin level)

Adcirca (Tadalafil)

Medication Trade Name	Tadalafil
Medication Generic Name	Adcirca
Family of Medication	Inhibitors of Phosphodiesterase type 5
Form of Medication	Tablets
Route of Delivery	Oral / by mouth
Dose	20-40 mg
Dosing frequency	once daily
Health Canada Approval Date	February 2010
Approved for what types of PH?	WHO Group I PAH
Approved for what severity of PH?	WHO Functional Class II-III
Demonstrated Beneficial Effects	Increased exercise capacity (6 minute walk distance) Increased time to clinical worsening Decreased incidence of clinical worsening Improved health related quality of life
Side Effects and Risks	Tadalafil is generally well tolerated. The most frequent side effects are: Headache Muscle pain Nasal stuffiness Flushing of the skin Respiratory infection Leg or arm pain Nausea Back pain Upset stomach A reduction in blood pressure throughout the body may occur because tadalafil relaxes blood vessels (arteries) throughout the body. Caution must be used in patients with low blood pressure- - for example, less than 90/50 mmHg. Caution is also needed in patients with dehydration, left-sided heart diseases and certain abnormalities of the body's nervous system function. Taking certain medications such as nitrates, nitric oxide donors or alpha blockers along with tadalafil can cause a significant drop in blood pressure. This could result in loss of consciousnessor even death. You should make certain that you are not taking these medications before starting tadalafil. Use of tadalafil with medications known as nitrates is CONTRAINDICATED. Prolonged erection (greater than four hours) in a male patient is a rare but very serious side effect; if this should happen to you, you should go to an emergency room or contact your doctor immediately. Sudden loss of vision in one or both eyes has occurred in patients on PDE5 inhibitors. Such an event may represent serious dysfunction of the optic nerve and requires immediate medical attention. Sudden loss of hearing may occur and may be accompanied by dizziness and/or ear ringing. Patients should seek prompt medical attention should this occur.

Opsumit (Macitentan)

Medication Trade Name	Macitentan
Medication Generic Name	Opsumit
Family of Medication	Endothelin Receptor Antagonists (ERAs)
Form of Medication	Tablets
Route of Delivery	Oral / by mouth
Dose	10mg
Dosing frequency	daily
Health Canada Approval Date	November 2013
Approved for what types of PH?	WHO Group I PAH
Approved for what severity of PH?	WHO Functional Class II-III
Demonstrated Beneficial Effects	XXXXXXXXXX
Side Effects and Risks	Macitentan is generally well tolerated. The most frequent side effects are: Nasal inflammation (stuffy nose) Headache Anemia Bronchitis (irritation of the airways) Urinary tract infection Flu-like illness Macitentan can cause serious birth defects if taken during pregnancy. Liver problems can occur with ERAs like macitentan. Low red blood cell levels can occur during the first weeks after starting therapy. In some cases, a blood transfusion may be needed, but this is not common. Changes in sperm production may result in men taking macitentan, based on the effects of the medication that was observed in animals. Men taking macitentan should discuss this further with their health care provider. Fluid retention is a known side effect of ERAs. It is important to notify your physician if you experience swelling or any other side effects. Treatment may be required including reducing salt and fluid in your diet, as well as a water pill (diuretic) to promote increased fluid removal through the kidneys.

Adempas (Riociguat)

Medication Trade Name	Riociguat
Medication Generic Name	Adempas
Family of Medication	Soluble guanylate cyclase stimulators
Form of Medication	Tablets
Route of Delivery	Oral / by mouth
Dose	0.5mg, 1mg, 1.5mg, 2mg, 2.5mg
Dosing frequency	three times daily
Health Canada Approval Date	March 2014
Approved for what types of PH?	WHO Group 1 patients, WHO Group 4 patients having chronic thromboembolic pulmonary hypertension (CTEPH) that is recurrent/persistent after surgical treatment or inoperable.
Approved for what severity of PH?	WHO Functional Class II-III
Demonstrated Beneficial Effects	XXXXXXXXXX
Side Effects and Risks	Riociguat is generally well tolerated. The most frequent side effects are: Headache Upset stomach Dizziness Nausea Diarrhea Low blood pressure Vomiting Anemia Gastroesphageal reflux (Known as GERD or heartburn) Constipation Other side effects include: Palpitations Nasal congestion Nosebleeds Difficulty swallowing Abdominal swelling Edema (Swelling in feet) A reduction in blood pressure throughout the body may occur because riociguat relaxes blood vessels (arteries) throughout the body. Caution must be used in patients taking blood pressure medicines, medicines that might interact with riociguat, or if they have low blood pressure. Caution is also needed in patients with dehydration, left-sided heart diseases and certain abnormalities of the body's nervous system function. Serious bleeding is rarely seen in patients taking riociguat.

Other treatments

Some patients with PH can have swelling of their feet or ankles (also known as edema). In these patients, medications are used to help the kidneys eliminate fluid from the body (also known as diuretics): Diuretics include:

Furosemide (Lasix, Apo-furosemide): typically 20 or 40 mg tablets, taken once or twice daily by mouth. Side effects can include low blood pressure, dizziness, fainting, kidney failure, and low potassium or low sodium in the blood.
Metolazone (Zaroxylyn): typically 2.5 or 5 mg, taken every few days, daily, or twice daily by mouth. Side effects can include low blood pressure, dizziness, fainting, kidney failure, and low potassium or low sodium in the blood.
Spironolactone (Aldactone, Novo-Spiroton): typically 25 or 50 mg, taken once or twice daily by mouth. Side effects can include low blood pressure, dizziness, fainting, kidney failure, painful breasts in men, and high potassium in the blood.
Hydrochlorothiazide (apo-thiazide, HCTZ): typically 12.5-25 mg taken once a day. Side effects can include low blood pressure, dizziness, fainting, kidney failure, and low potassium or low sodium in the blood.

Some patients with PH should be treated with blood thinners (also known as anti-coagulants). Anti-coagulant medications include:

Coumadin (Warfarin): typically from 1 to 10 mg, taken once daily by mouth. Side effects can include bleeding, which can be severe in 1-2% of patients every year. Coumadin interacts with many other medications, such as antibiotics.
Low-molecular weight heparins (Fragmin = dalteparin, Lovenox = enoxaparin, Fraxiparin = nadroparin, Innohep = tinzaparin, Logiparin= tinzaparin). Various doses of the different drugs are given once or twice daily, by injection under the skin (also known as sub-cutaneously). Side effects can include bleeding.
The utility of newer anticoagulants (rivaroxiban, dabigatran, apixaban) in pulmonary hypertension remains undetermined.

Some patients with PH have weakness of the right side of the heart. This may occasionally be treated with digoxin, a medication that supports the right side of the heart, and may help to reduce the symptoms of right heart failure.

The typical dose of digoxin is 0.0625 mg to 0.25 mg taken once a day. Your doctor may follow the levels of digoxin in your blood to determine the right dose for you.

Side effects of digoxin include: dizziness, fainting, fast or irregular heart rate, nausea and vomiting, slowing of heart rate, headache and changes in your vision.

Some patients with PH have low oxygen levels in the blood. Low oxygen levels can make PH worse.

In some of these patients, oxygen is used to improve blood oxygen levels.
Some patients need to wear oxygen continuously. Other patients may only need oxygen while sleeping, or while exercising.
Extra or supplemental oxygen is given to patients through tubing worn in the nose (nasal cannulae) or a breathing mask.
Oxygen is delivered by a machine which takes oxygen out of the air (also known as concentrator), or from a tank of liquid oxygen (also known as cylinder).
Typical doses are 1-6 liters per minute of oxygen, or 24 – 60% oxygen.

Some patients with PH are treated with medications that relax and open pulmonary arteries (also known as vasodilators). Vasodilator medications mainly include a family of drugs known as calcium-channel blockers (CCBs). CCBs used to treat PH include:

Diltiazem (Cardizem, Tiazac)
Amlodipine (Norvasc)
Nifedipine (Adalat, Procardia)

Side-effects can include low blood pressure, dizziness, fainting, slow or fast pulse, worse swelling of the feet or ankles.

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