Tadalafil dosage, forms, and strengths

The most common side effects with tadalafil tablets include:

Tadalafil (Oral Tablet): Side Effects, Dosage, and Review

Tadalafil oral tablet doesn’t usually cause drowsiness, but it can cause other side effects.

More common side effects

The more common side effects that can occur with tadalafil include:

headache
upset stomach
back pain
muscle aches
flushing (reddish skin)
stuffy or runny nose
diarrhea

If these effects are mild, they may go away within a few days or a couple of weeks. If they’re more severe or don’t go away, talk with your doctor or pharmacist.

Serious side effects

Call your doctor right away if you have serious side effects. Call 911 if your symptoms feel life threatening or if you think you’re having a medical emergency. Serious side effects and their symptoms can include the following:

Priapism (in men). Symptoms can include:

a painful erection that won’t go away

seeing a shade of blue when looking at objects
trouble telling the difference between the colors blue and green
a sudden decrease or loss of vision in one or both eyes

a sudden loss or decrease in hearing
ringing in the ears
dizziness

feeling lightheaded or dizzy
fainting
angina (chest pain

Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs affect each person differently, we cannot guarantee that this information includes all possible side effects. This information is not a substitute for medical advice. Always discuss possible side effects with a healthcare provider who knows your medical history.

Tadalafil is a prescription drug. It comes as an oral tablet.

Tadalafil oral tablet is available as the brand-name drugs Cialis and Adcirca. It’s also available in a generic form. Generic drugs usually cost less than the brand-name version. In some cases, they may not be available in all strengths or forms as the brand-name drug.

Why it’s used

Tadalafil (Cialis) is used for treatment of benign prostatic hyperplasia (BPH) or erectile dysfunction (ED), or both conditions. Tadalafil (Adcirca) is used to treat pulmonary arterial hypertension (PAH).

With BPH, the prostate gland is enlarged but isn’t cancerous. It can pinch or squeeze your urethra (the tube that carries urine from the kidneys out of the body). Symptoms of BPH include trouble urinating, painful urination, and a frequent or urgent need to urinate.

With ED, the penis doesn’t fill up with enough blood to harden and expand when a man is sexually excited. ED can also prevent a man from keeping an erection.

PAH is a rare but serious form of high blood pressure. It occurs in the pulmonary arteries, which are blood vessels in your lungs.

How tadalafil is used

How long before sex should you take tadalafil? Tadalafil can be prescribed in two different ways, either a daily dosage or on an as-needed basis. Your doctor will prescribe either one. If you’re taking tadalafil on an as-needed basis, you should take it at least 30 minutes before sex. If you’re taking it daily, try to take it around the same time every day.

How often should you take tadalafil? Tadalafil should not be taken more than once in a 24-hour period. If you miss a dose during this period, take the missed dose as soon as possible. However, never double your dosages. If you miss a dose and you’re already due for the next one, skip the missed dose.

Should tadalafil be taken with food? Tadalafil can be taken with or without food and is not affected by the type of food you take with it.

How it works

Tadalafil belongs to a class of drugs called phosphodiesterase type 5 (PDE5) inhibitors. A class of drugs is a group of medications that work in a similar way. These drugs are often used to treat similar conditions.

Tadalafil may help relax the muscle in your prostate and bladder. This could help improve your BPH symptoms.

To improve ED symptoms, tadalafil helps increase blood flow to the penis. This can help you get and keep an erection. For tadalafil to help you have an erection, you need to be sexually aroused.

For PAH, tadalafil works to improve your ability to exercise by relaxing blood vessels in your lungs. This increases blood flow.

Heart disease warning. You shouldn’t use tadalafil if you have a heart condition and your doctor has advised against sexual activity. Call your doctor right away if you have symptoms during sex such as chest pain, dizziness, or nausea. Sexual activity can put an extra strain on your heart. This is especially true if your heart is already weak from a heart attack or heart disease.
Priapism warning.Priapism is an erection that won’t go away. Without treatment, this condition could cause permanent damage to your penis. This damage includes impotence (not being able to have an erection). If you get an erection that lasts more than 4 hours, call your doctor right away.

Tadalafil oral tablets can interact with other medications, vitamins, or herbs you may be taking. An interaction is when a substance changes the way a drug works. This can be harmful or prevent the drug from working well.

To help avoid interactions, your doctor should manage all of your medications carefully. Be sure to tell your doctor about all medications, vitamins, or herbs you’re taking. To find out how this drug might interact with something else you’re taking, talk with your doctor or pharmacist.

Examples of drugs that can cause interactions with tadalafil are listed below.

Angina drugs (nitrates)

If you take tadalafil with nitrates, your blood pressure could suddenly drop to dangerously low levels. This could make you dizzy or cause you to faint. Examples of nitrates include:

High blood pressure or prostate drugs (alpha-blockers)

If you take tadalafil with certain alpha-blockers, your blood pressure could suddenly drop to low levels that are dangerous. This could make you dizzy or cause you to faint. Examples of these drugs include:

Certain HIV drugs

Taking tadalafil with certain HIV drugs could increase tadalafil levels in your blood. This can lead to low blood pressure, dizziness and fainting, and vision problems. In men, it can also lead to priapism. These drugs are protease inhibitors and include ritonavir and lopinavir/ritonavir.

Oral antifungal drugs

Taking certain antifungal drugs with tadalafil may increase levels of tadalafil in your blood. This can lead to low blood pressure, dizziness and fainting, and vision problems. In men, it can also lead to priapism. Examples of these drugs include ketoconazole and itraconazole.

Antibiotics

Taking certain antibiotics with tadalafil may raise the level of tadalafil in your blood. This can lead to low blood pressure, dizziness and fainting, and vision problems. In men, it can also lead to priapism. Examples of these drugs include:

Other types of antibiotics may lower the level of tadalafil in your blood. This could prevent tadalafil from working well. This includes drugs such as rifampin.

Other erectile dysfunction (ED) drugs

These medications work in the same way as tadalafil. If you take them with tadalafil, it increases your risk for side effects. Examples of these drugs include sildenafil and vardenafil.

Other pulmonary arterial hypertension (PAH) drugs

If you take tadalafil with other types of PAH drugs, your blood pressure could suddenly drop to dangerously low levels. The drug riociguat is in this drug class.

Stomach acid drugs

Taking these medications with tadalafil may keep your body from absorbing tadalafil well. An example of this type of drug is magnesium hydroxide/aluminum hydroxide.

Epilepsy drugs

Taking certain anti-seizure drugs with tadalafil may lower the level of tadalafil in your blood. This could prevent tadalafil from working well. Examples of these drugs include:

Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs interact differently in each person, we cannot guarantee that this information includes all possible interactions. This information is not a substitute for medical advice. Always speak with your healthcare provider about possible interactions with all prescription drugs, vitamins, herbs and supplements, and over-the-counter drugs that you’re taking.

Allergy warning

Tadalafil can cause a severe allergic reaction. Symptoms can include:

If you develop these symptoms, call 911 or go to the nearest emergency room.

Don’t take this drug again if you’ve ever had an allergic reaction to it. Taking it again could be fatal (cause death).

Grapefruit interaction warning

Eating grapefruit or drinking grapefruit juice may increase the levels of tadalafil in your blood. This raises your risk for side effects.

Alcohol interaction warning

Don’t drink large amounts of alcohol when taking tadalafil. Both alcohol and tadalafil can dilate (widen) your blood vessels. When used together, they can cause your blood pressure to drop.

Warnings for people with certain health conditions

For people with heart disease: Sexual activity creates a risk for your heart. Using tadalafil may increase that risk. Don’t use tadalafil if you have a heart condition and your doctor has advised against sexual activity.

For people at risk for prolonged erections: Tadalafil may cause priapism. This condition causes a painful, long-lasting erection. It is a medical emergency. Talk with your doctor before using tadalafil if you have a condition that puts you at higher risk for priapism. These conditions include blood cell conditions such as sickle cell anemia, multiple myeloma, or leukemia Peyronie’s disease (a curved or deformed penis).

For people with vision problems: Retinitis pigmentosa is a rare genetic eye disease. Tadalafil hasn’t been studied in people with this condition, and its use isn’t recommended. Tell your doctor if you’ve ever had severe vision loss, including a condition called NAION (non-arteritic anterior ischemic optic neuropathy). If you’ve had NAION and take tadalafil, you may be at increased risk for having NAION again.

For people with kidney disease or on dialysis: Your body may not be able to get rid of tadalafil correctly. This means the drug would stay in your body longer and raise your risk for side effects. Your doctor may start you on a lower dosage, have you take it less often, or not prescribe it at all.

For people with liver problems: Your body may not process tadalafil correctly. This means the drug would stay in your body longer and raise your risk for side effects. Your doctor may start you on a lower dosage, have you take it less often, or not prescribe it at all.

For people with bleeding disorders or peptic ulcers: Tadalafil hasn’t been studied in people with these conditions. Using tadalafil may cause or worsen bleeding or ulcers. If you take tadalafil, your doctor may monitor you more closely.

Warnings for other groups

For pregnant women: Studies of this drug in pregnant animals haven’t shown risk to the fetus. However, there aren’t enough studies done in pregnant women using the drug for PAH to show whether the drug poses a risk to a human fetus.

Talk with your doctor if you’re pregnant or planning to become pregnant. Animal studies don’t always predict the way humans would respond. Therefore, this drug should only be used in pregnancy if clearly needed.

For women who are breastfeeding: It isn’t known if tadalafil passes into breast milk. If it does, it may cause serious effects in a child who is breastfed. Talk with your doctor if you’re taking tadalafil and you want to breastfeed.

For seniors: If you are age 65 years or older, your body may process this drug more slowly. Your doctor may start you on a lower dosage so that tadalafil doesn’t build up too much in your body. High levels of the drug in your body can be dangerous.

For children: Children younger than 18 years old shouldn’t use tadalafil. It’s not known if tadalafil is safe and effective in children.

Tadalafil dosage, forms, and strengths

Tadalafil is a generic prescription drug that is used to treat pulmonary arterial hypertension, erectile dysfunction (ED), or the lower urinary tract symptoms of prostate enlargement (benign prostatic hyperplasia or BPH). Tadalafil is only available as a tablet and is taken by mouth once a day with or without food. Although sold as a generic drug, tadalafil is also available as two well-known brand-name drugs—Cialis and Adcirca. Cialis is sold in tablet strengths appropriate for erectile dysfunction and enlarged prostate. Adcirca comes in strengths suitable to treat pulmonary hypertension.

Tadalafil belongs to a family of drugs called PDE5 inhibitors, or “phosphodiesterase type 5 inhibitors.” These drugs relax the smooth muscles in blood vessels, particularly arteries, causing them to widen. This lowers blood pressure in pulmonary arteries, alleviating pulmonary hypertension, and increases and prolongs blood flow to the penis, helping to improve men’s sexual function. PDE5 inhibitors also relax muscles in the bladder and lower urinary tract, helping to relieve urinary symptoms in men with prostate enlargement.

Tadalafil dosage, forms, and strengths

Tadalafil dosage for adults

Tadalafil is taken once a day for pulmonary hypertension or BPH. It can be taken daily or as needed for erectile dysfunction.

Standard dosage for adults: 2.5–5 mg (BPH or ED) or 40 mg (pulmonary arterial hypertension) once per day or 5–20 mg as needed (ED)
Maximum dosage for adults: No more than 20 mg per day (BPH or ED) or 40 mg per day (pulmonary hypertension)

Tadalafil dosage chart
Indication	Starting dosage	Standard dosage	Maximum dosage
Erectile dysfunction (as needed)	10 mg taken before sexual activity	5–20 mg taken before sexual activity	No more than 20 mg per day
Erectile dysfunction (once daily)	2.5 mg once per day	2.5–5 mg once per day	5 mg once per day
Benign prostatic hyperplasia with or without erectile dysfunction	5 mg once per day	5 mg once per day	Not specified
Pulmonary arterial hypertension	40 mg once per day	40 mg once per day	Not specified

Tadalafil dosage for children

Tadalafil has not been approved by the FDA for use in people younger than 18 years of age.

As-needed dosage for erectile dysfunction

As a treatment of erectile dysfunction, tadalafil can be taken as needed to improve sexual function. Prescriptions will typically come in 5 mg, 10 mg, and 20 mg strengths. The starting dose is typically started at 10 mg, but this dose may be reduced to 5 mg or increased to as much as 20 mg depending on the effectiveness and tolerability of the starting dose.

Adults (18 years and older): 5–20 mg taken before anticipated sexual activity

Renally impaired patients (kidney disease)—dose amount adjustment:

Creatinine clearance of 30–50 milliliters (ml)/min: 5-10 mg once per day to a maximum of 10 mg every 48 hours
Creatinine clearance less than 30 ml/min: 5 mg every 72 hours
Hemodialysis: 5 mg every 72 hours, no supplement after dialysis
Peritoneal dialysis: Not defined

Mild to moderate hepatic impairment: Use with caution; 5–10 mg to a maximum of 10 mg every 24 hours

Daily dosage for erectile dysfunction

Alternatively, tadalafil can be taken daily at a lower dose to treat erectile dysfunction. Sexual activity can be engaged in at any time between doses.

Adults (18 years and older): 2.5–5 mg taken once per day

Renally impaired patients (kidney disease):

Creatinine clearance less than 30 ml/min: Not recommended
Hemodialysis: Not recommended
Peritonealdialysis: Not defined

Mild to moderate hepatic impairment: Use with caution
Severe hepatic impairment: Not recommended

Dosage for symptoms of benign prostatic hyperplasia (BPH)

Tadalafil is prescribed as a daily dose to alleviate lower urinary tract symptoms due to benign prostatic hyperplasia, often in combination with other drugs such as finasteride. Erectile dysfunction may also be experienced by men with enlarged prostates, so a daily tadalafil dose can treat both conditions.

Adults (18 years and older): 5 mg taken once per day

Renally impaired patients (kidney disease)—dose amount adjustment:

Creatinine clearance of 30–50 ml/min: 2.5–5 mg once per day
Creatinine clearance less than 30 ml/min: Not recommended
Hemodialysis: Not recommended
Peritonealdialysis: Not defined

Mild to moderate hepatic impairment: Use with caution
Severe hepatic impairment: Not recommended

Dosage for pulmonary arterial hypertension

Tadalafil is used to improve exercise ability in people with pulmonary arterial hypertension. The dose, however, is higher than it is for other indications: 40 mg once per day. People with pulmonary hypertension, then, will receive prescriptions for 20 mg tadalafil tablets specifically indicated for pulmonary hypertension.

Adults (18 years and older): 40 mg taken once per day

Renally impaired patients (kidney disease)—dose amount adjustment:

Creatinine clearance of 30–50 ml/min: 20–40 mg once per day
Creatinine clearance less than 30 ml/min: Avoid use
Hemodialysis: Avoid use
Peritoneal dialysis: Not defined

Mild to moderate hepatic impairment: Use with caution; consider starting dose 20 mg once per day
Severe hepatic impairment: Avoid use

Tadalafil dosage for pets

The FDA has not approved tadalafil for use in animals. Some veterinarians, however, may prescribe tadalafil to dogs for pulmonary hypertension. The research, however, is limited. For this reason, no standard veterinary dosages have been defined, so individual practitioners may prescribe different doses based on their experience. Do not, however, give tadalafil or any other human prescription drug to a pet except under the direction of a veterinarian. The dose may be wrong, and one or more of the inactive ingredients may be harmful to the animal.

How to take tadalafil

Tadalafil is taken by mouth as a tablet with or without food. It will be prescribed either as a once-daily dose or on an as-needed basis.

Only take tadalafil with a prescription and under the care of a healthcare provider. Take the medicine as directed by a healthcare provider.
Swallow the tablet whole. Do not crush or chew it.
Do not take more than one dose per day or split the dose into two daily doses.
For daily use, the tadalafil dose should be taken at the same time each day.
Carefully read and follow the patient information brochure that comes with the prescription.
For erectile dysfunction, sexual activity can be initiated any time from 30 minutes to 36 hours after taking tadalafil.
For erectile dysfunction, sexual stimulation is required for an erection.
Drinking alcohol within 36 hours of a tadalafil dose may lower blood pressure, so alcohol use is best avoided.
If too much tadalafil is taken, seek immediate medical advice.
Always check the expiration date. If the expiration date has passed, dispose of the medication safely and get a new prescription.
Tadalafil should be stored at room temperature. Check the patient information brochure for the ideal temperature range.

Tadalafil dosage FAQs

How long does it take tadalafil to work?

When taken orally, tadalafil quickly enters the bloodstream and hits maximum concentration in the blood within 30 minutes to six hours. Its bioavailability and immediate effectiveness are not affected by food.

How long does tadalafil stay in your system?

Tadalafil lasts for a long-time in the body. With a half-life of 17.5 hours for healthy people and up to 35 hours for people with pulmonary hypertension, a single dose of tadalafil can take four days or more to clear out of the body. This is why tadalafil is often nicknamed “the weekend pill”: its effects when treating erectile dysfunction can persist for up to 36 hours.

What happens if I miss a dose of tadalafil?

A missed dose can be taken when remembered, but do not take more than one dose in a single day. People with pulmonary hypertension will usually have to take two 20 mg pills each day. Do not divide these two pills into two separate doses. Take them at the same time. Never take extra doses of tadalafil to make up for a missed dose.

How do I stop taking tadalafil?

Tadalafil does not create physical dependency, though men using tadalafil in excess without a prescription may feel psychologically dependent on the medication. Tadalafil can be discontinued without withdrawal symptoms or any need for tapered dosing. However, patients with pulmonary hypertension should check with their healthcare provider before stopping tadalafil.

Some circumstances may require people to immediately stop taking tadalafil, especially any sudden loss of vision in one or both eyes or sudden hearing loss, both of which will require emergency medical treatment. Any allergic reaction to the drug such as hives, rash, trouble breathing, or swelling around the face or throat is a signal the medicine should be stopped until the cause of the reaction can be determined.

What is the maximum dosage for tadalafil?

Men taking tadalafil for erectile dysfunction should not take more than 20 mg per day. The recommended daily dose for pulmonary hypertension is 40 mg per day and should not be exceeded. Excessive doses significantly raise the risk of dangerously low blood pressure, prolonged and painful erections, cardiovascular changes, and vision or hearing loss.

What interacts with tadalafil?

Food doesn’t affect the body’s ability to absorb tadalafil. However, avoid grapefruit or grapefruit juice. Grapefruit has substances that hamper the ability of the body to break down tadalafil.

Tadalafil is metabolized by the enzyme CYP3A4. Numerous other medications can increase or decrease the activity of this enzyme, which can lead to heightened or reduced activity of tadalafil. Have your healthcare provider review your medication list to determine if any of these medication interaction concerns pertain to you. Certain blood pressure medications, such as alpha blockers, and erectile dysfunction drugs similar to tadalafil like sildenafil, available as Viagra or Revatio, and vardenafil, sold under the brand name Levitra, should also be avoided due to the potential for reduced blood pressure if taken together with tadalafil. Anyone taking nitrates, which are used for chest pain, heart conditions, and high pressure, should typically avoid tadalafil. Talk to your healthcare provider about all possible interactions and if tadalafil is right for you.

Resources

Related Drugs

Related Conditions

Tadalafil Dosage Forms

10 mg PO as needed before anticipated sexual activity. May decrease the dose to 5 mg or increase the dose to 20 mg PO as needed before anticipated sexual activity. Max: 1 dose/day and 20 mg/dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

2.5 mg PO once daily. May increase the dose to 5 mg/day if needed. Max: 5 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

5 mg PO once daily, taken at approximately the same time every day, without regard to timing of sexual activity. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

5 mg PO once daily. When therapy for BPH is initiated concurrently with finasteride, use for up to 26 weeks. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of pulmonary hypertension to improve exercise ability in persons with WHO Group I pulmonary hypertension.

20 or 40 mg PO once daily, initially. Increase dose to 40 mg PO once daily as tolerated. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Efficacy studies primarily included people with NYHA functional Class II to III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%).[40259]

0.5 to 1 mg/kg/dose PO once daily, initially. Increase dose as tolerated. Max: 40 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

10 mg PO twice daily starting the day before ascent and continuing for 5 days after reaching the target altitude or until descent is initiated as an alternative to nifedipine.[56782] Prophylactic medications should only be considered for individuals with a history of high altitude pulmonary edema.[56782]

Maximum Dosage

40 mg/day PO for pulmonary hypertension; 5 mg/day PO for erectile dysfunction for once daily use; 20 mg/dose PO for erectile dysfunction for as needed use, not to exceed 1 dose/24 hours in most patients; 5 mg/day PO for benign prostatic hyperplasia (BPH) or combined treatment of erectile dysfunction/BPH for once daily use.

Safety and efficacy have not been established.

Dosing Considerations

Erectile Dysfunction (ED) for use as needed
Mild to moderate impairment (Child-Pugh class A or B): Do not exceed 10 mg PO once daily.
Severe impairment (Child-Pugh class C): Tadalafil is not recommended.

Erectile Dysfunction (ED), Benign Prostatic Hypertrophy (BPH), or Erectile Dysfunction (ED) with Benign Prostatic Hypertrophy (BPH) for once daily use
Mild to moderate impairment (Child-Pugh class A or B): Use with caution; usually do not exceed 10 mg PO once daily as is recommended with “as needed” use. Use of tadalafil once daily has not been extensively evaluated in patients with hepatic impairment.
Severe impairment (Child-Pugh class C): Tadalafil is not recommended.

Pulmonary Arterial Hypertension (PAH)
Mild to moderate impairment (Child-Pugh class A or B): Consider an initial dose of 20 mg PO once daily; limited data available for use in this patient population.
Severe impairment (Child-Pugh class C): Avoid use of tadalafil.

Erectile Dysfunction (ED) for use as needed
CrCl 51 mL/minute or more: No dosage adjustment needed.
CrCl 30 to 50 mL/minute: A starting dose of 5 mg PO not more than once per day is recommended. Max: 10 mg PO not more than once per every 48 hours.
CrCl less than 30 mL/ minute: Do not exceed 5 mg PO once every 72 hours; once daily use is not recommended.

Erectile Dysfunction (ED) for once daily use
CrCl 30 to 50 mL/minute: Dosage adjustment may be needed.
CrCl less than 30 mL/ minute: Once daily use is not recommended.

Benign Prostatic Hypertrophy (BPH) with or without Erectile Dysfunction (ED) for once daily use
CrCl 51 mL/minute or more: No dosage adjustment needed.
CrCl 30 to 50 mL/minute: Initially, 2.5 mg PO once daily. An increase to 5 mg PO once daily may be considered based on individual response.
CrCl less than 30 mL/ minute: Tadalafil is not recommended for once daily use.

Pulmonary Arterial Hypertension (PAH)
CrCl more than 80 mL/minute: No dosage adjustment needed.
CrCl 51 to 80 mL/minute: 20 mg PO once daily, initially. Max: 40 mg PO once daily.
CrCl 30 to 50 mL/minute: 20 mg PO once daily, initially. Max: 40 mg PO once daily.
CrCl less than 30 mL/minute: Avoid use of tadalafil.

Intermittent hemodialysis
The maximum recommended dose in patients with ED receiving tadalafil for use as needed for ED is 5 mg PO given not more than once every 72 hours. Not recommended for once daily use for ED, BPH, a combination of ED and BPH, or for PAH.

Administration

May be administered without regard to meals.

Oral Tablets for pulmonary hypertension (e.g., Adcirca, Alyq)
Administer the entire dose once daily; do not give in divided doses over the course of the day.

Oral Tablets for erectile dysfunction (ED) and/or benign prostatic hypertrophy (BPH) (e.g., Cialis)
For as needed use for ED: Instruct patient to take dose at least 30 minutes before anticipated sexual activity. In most patients, the ability to have sexual intercourse is improved for up to 36 hours.
For once daily use for ED: Inatruct patient to take at approximately the same time each day, without regard to timing of sexual activity.
For once daily use for benign prostatic hyperplasia: Administer at approximately the same time each day.
For once daily use for those with combined ED and BPH: Administer at approximately the same time each day, without regard to timing of sexual activity.

Oral Suspension for pulmonary arterial hypertension (e.g., Tadliq):
Administer once daily at the same time each day.
Shake well for 30 seconds before measuring the daily dose. To ensure accurate dosing, measure dosage with calibrated spoon, cup, or oral syringe.

Storage

Adcirca:
– Store at 77 degrees F; excursions permitted to 59-86 degrees F
ALYQ:
– Store at 77 degrees F; excursions permitted to 59-86 degrees F
Cialis:
– Store at 77 degrees F; excursions permitted to 59-86 degrees F
Tadliq:
– Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

Contraindications / Precautions

Tadalafil is contraindicated in patients with a known hypersensitivity to the drug or any component of the tablet.[40259] [28220]

The safety and efficacy of combinations of tadalafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.[28220]

Because the efficacy of concurrent use of tadalafil and alpha-blockers in the treatment of benign prostatic hyperplasia (BPH) has not been adequately studied and due to the potential vasodilatory effects of such combination treatment, tadalafil is not recommended for use with alpha-blockers when treating BPH.[28220]

Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy or guanylate cyclase (GC) stimulators therapy, such as riociguat. Consistent with its known effects on the nitric oxide/cGMP pathway, tadalafil may potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive tadalafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once tadalafil has been administered for erectile dysfunction. When tadalafil is administered for pulmonary arterial hypertension, nitrates should not be administered within 48 hours after the last tadalafil dose. Tadalafil may potentiate the hypotensive effects of GC stimulators.[28220] [40259]

Avoid use of tadalafil for pulmonary arterial hypertension or benign prostatic hyperplasia as well as daily use in erectile dysfunction in patients with renal failure or severe renal impairment (CrCl less than 30 mL/minute), including dialysis-dependence, due to increased tadalafil exposure, limited clinical experience, and lack of ability to influence clearance by dialysis. Starting dose modifications and dosage limits may apply for patients with mild or moderate renal impairment.[28220] [40259]

Avoid use of tadalafil in patients with severe hepatic disease (Child-Pugh Class C). Tadalafil has not been studied in patients with cirrhosis. Cautious use and starting dose modifications are recommended in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B).[28220] [40259]

Angina, cardiac arrhythmias, coronary artery disease, heart failure, hypertension, hypotension, myocardial infarction, stroke, veno-occlusive disease (VOD)

There is a degree of cardiac risk associated with sexual activity; therefore, consider cardiovascular status of the patient before initiating tadalafil for erectile dysfunction. Do not use tadalafil in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status. Educate patients who experience symptoms upon initiation of sexual activity to refrain from further sexual activity, and advise any patient experiencing anginal chest pain after taking tadalafil for any indication to seek immediate medical attention. Tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Before starting tadalafil, carefully consider whether patients with underlying cardiovascular disease could be adversely affected by such vasodilatory effects. Patients with severely impaired autonomic control of blood pressure or with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) may be particularly sensitive to vasodilators, including PDE5 inhibitors. Tadalafil use for erectile dysfunction or benign prostatic hypertrophy is not recommended for the following patient groups due to lack of safety and efficacy data: myocardial infarction within the last 90 days; unstable angina or angina occurring during sexual intercourse; NYHA Class II or greater heart failure in the last 6 months; uncontrolled cardiac arrhythmias; hypotension (less than 90/50 mmHg); uncontrolled hypertension; or a stroke within the last 6 months. Additionally, there is a lack of safety and efficacy data in the treatment of pulmonary arterial hypertension due to exclusion from clinical trials for the following patient groups: aortic and mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, significant left ventricular dysfunction, life-threatening arrhythmias, symptomatic coronary artery disease, hypotension (less than 90/50 mmHg), or uncontrolled hypertension. Further, tadalafil is not recommended for use in patients with pulmonary veno-occlusive disease (VOD) since there are no clinical data. Due to the pulmonary vasodilation caused by tadalafil, patients with pulmonary VOD may experience significant worsening in cardiovascular status. If signs of pulmonary edema occur with tadalafil administration, consider the possibility of associated pulmonary VOD.[28220] [40259]

Leukemia, multiple myeloma, penile structural abnormality, Peyronie’s disease, polycythemia, priapism, sickle cell disease

Prolonged erections more than 4 hours and priapism (painful erections more than 6 hours) have been associated with PDE5 inhibitor administration. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting more than 4 hours, whether painful or not, should seek emergency medical attention. Use tadalafil with caution in patients with a penile structural abnormality, such as angulation, cavernosal fibrosis, or Peyronie’s disease, or with conditions predisposing to priapism, such as sickle cell disease, leukemia, multiple myeloma, polycythemia, or history of priapism.[28220] [40131]

Educate patients that use of tadalafil for erectile dysfunction offers no protection against sexually transmitted disease. Counsel patients about protective measures necessary to guard against sexually transmitted diseases, including human immunodeficiency virus (HIV) infection.[28220]

Patients with sudden visual impairment, such as loss of vision in one or both eyes, should stop using tadalafil immediately and seek medical attention. Postmarketing reports of sudden vision loss, including permanent vision loss, have occurred with PDE5 inhibitors like tadalafil. Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve. Most of the patients who developed NAION had underlying anatomic or vascular risk factors for the development of NAION, including, but not limited to, low cup to disc ratio (“crowded disc”), age older than 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Advise patients of the increased risk of NAION if they have already experienced NAION in 1 eye. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in clinical trials; tadalafil use is not recommended in these patients.[28220] [40259]

Use tadalafil cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Tadalafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.[26879]

Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), which is found in platelets. Some data indicate that tadalafil does not potentiate the increase in bleeding time caused by aspirin. However, tadalafil has not been studied in patients with bleeding disorders or significant active peptic ulcer disease. Carefully assess risk-benefit and use tadalafil with caution in patients with significant hematological disease (e.g., bleeding disorders) or significant active peptic ulceration.[28220]

Before initiating treatment with tadalafil for benign prostatic hyperplasia (BPH), consider other urological conditions that may cause similar symptoms, such as prostate cancer. Prostate cancer and BPH cause many of the same symptoms and frequently coexist.[28220]

Available data from a randomized controlled trial, observational studies, and case series with tadalafil administration during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies in rats and mice at exposures of 7 times the maximum recommended human dose (MRHD) of 40 mg/day based on AUC revealed no evidence of teratogenicity, embryotoxicity, or fetotoxicity. In a perinatal/postnatal development study involving rats, a reduction in postnatal pup survival occurred with doses of 60 mg/kg, 200 mg/kg, and 1,000 mg/kg. The no-observed-effect-level (NOEL) for development toxicity was 30 mg/kg, which was 5 times the MRHD. Maternal toxicity was observed at 200 mg/kg, which was 8 times the MRHD. Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. It is recommended that women with pulmonary arterial hypertension avoid becoming pregnant.[40259]

There are no data on the presence of tadalafil or its metabolites in human breast milk, the effects on the breastfed child, or the effects on breast-feeding. Tadalafil or some metabolite of tadalafil was excreted in rat milk. Because many drugs are excreted in human breast milk, use tadalafil with caution in breast-feeding women. The developmental and health benefits of breast-feeding should be considered along with the mother’s need for tadalafil and any potential adverse effects on the breastfed child from tadalafil or the underlying maternal condition.[40259]

Decreased sperm concentration with tadalafil therapy was observed in 2 studies involving adult males who received tadalafil 10 mg for 6 months and 20 mg for 9 months; this effect was not seen in male patients in a third study taking tadalafil 20 mg for 6 months. Tadalafil did not have an adverse effect on testosterone, luteinizing hormone, or follicle-stimulating hormone. The clinical significance of the reductions in sperm count and whether it may result in infertility are not known. No studies have evaluated the effect of tadalafil on fertility in men or women.

Adverse Reactions

myocardial infarction / Delayed / 0-2.0
GI bleeding / Delayed / 0-2.0
hearing loss / Delayed / 0-2.0
stroke / Early / Incidence not known
seizures / Delayed / Incidence not known
retinal thrombosis / Delayed / Incidence not known
visual impairment / Early / Incidence not known
non-arteritic anterior ischemic optic neuropathy / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known

hypertension / Early / 1.0-3.0
palpitations / Early / 0-2.0
orthostatic hypotension / Delayed / 0-2.0
hypotension / Rapid / 0-2.0
angina / Early / 0-2.0
chest pain (unspecified) / Early / 0-2.0
sinus tachycardia / Rapid / 0-2.0
dysphagia / Delayed / 0-2.0
esophagitis / Delayed / 0-2.0
gastritis / Delayed / 0-2.0
elevated hepatic enzymes / Delayed / 0-2.0
dyspnea / Early / 0-2.0
conjunctivitis / Delayed / 0-2.0
blurred vision / Early / 0-2.0
edema / Delayed / 0-2.0
QT prolongation / Rapid / Incidence not known
amnesia / Delayed / Incidence not known
migraine / Early / Incidence not known
conjunctival hyperemia / Early / Incidence not known
priapism / Early / Incidence not known

headache / Early / 3.0-42.0
myalgia / Early / 1.0-14.0
dyspepsia / Early / 1.0-13.0
pharyngitis / Delayed / 1.0-13.0
infection / Delayed / 2.0-13.0
flushing / Rapid / 1.0-13.0
back pain / Delayed / 2.0-12.0
musculoskeletal pain / Early / 1.4-11.0
nausea / Early / 0-11.0
nasal congestion / Early / 2.0-9.0
influenza / Delayed / 2.0-5.0
cough / Delayed / 2.0-4.0
gastroesophageal reflux / Delayed / 0-3.0
syncope / Early / 0-2.0
arthralgia / Delayed / 0-2.0
insomnia / Early / 0-2.0
vertigo / Early / 0-2.0
dizziness / Early / 1.0-2.0
hypoesthesia / Delayed / 0-2.0
paresthesias / Delayed / 0-2.0
drowsiness / Early / 0-2.0
xerostomia / Early / 0-2.0
vomiting / Early / 0-2.0
abdominal pain / Early / 0-2.0
diarrhea / Early / 1.0-2.0
epistaxis / Delayed / 0-2.0
ocular pain / Early / 0-2.0
blepharedema / Early / 0-2.0
lacrimation / Early / 0-2.0
tinnitus / Delayed / 0-2.0
asthenia / Delayed / 0-2.0
fatigue / Early / 0-2.0
pruritus / Rapid / 0-2.0
hyperhidrosis / Delayed / 0-2.0
rash / Early / 0-2.0
urticaria / Rapid / Incidence not known
oligospermia / Delayed / Incidence not known

Drug Interactions

Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Acetaminophen; Chlorpheniramine; Phenylephrine : (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Acetaminophen; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Alfuzosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alfuzosin therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of alfuzosin; increases in the alpha-blocker dose should be done in a stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alfuzosin therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and alfuzosin.
Alpha-blockers: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
Amiodarone: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with amiodarone is necessary. Tadalafil is a CYP3A4 substrate and amiodarone is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Amyl Nitrite: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Aprepitant, Fosaprepitant: (Moderate) Use caution if tadalafil and aprepitant, fosaprepitant are used concurrently and monitor for an increase in tadalafil-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tadalafil is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of tadalafil. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Atazanavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of atazanavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of atazanavir therapy. Stop tadalafil at least 24 hours prior to starting atazanavir. After at least 1 week of atazanavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and atazanavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Atazanavir; Cobicistat: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily
administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4 (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of atazanavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of atazanavir therapy. Stop tadalafil at least 24 hours prior to starting atazanavir. After at least 1 week of atazanavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and atazanavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Berotralstat: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with berotralstat is necessary. Tadalafil is a CYP3A4 substrate and berotralstat is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Bosentan: (Moderate) Bosentan reduces tadalafil systemic exposure by 42% and Cmax by 27% with multiple-dose coadministration. Tadalafil has no significant effect on the exposure of bosentan. Bosentan is a substrate and moderate inducer of CYP3A; tadalafil is a CYP3A substrate.
Brompheniramine; Carbetapentane; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Brompheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Brompheniramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Carbamazepine: (Major) Avoid coadministration of tadalafil with carbamazepine in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of carbamazepine due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Carbetapentane; Chlorpheniramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Carbetapentane; Diphenhydramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Carbetapentane; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Carbetapentane; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Carbetapentane; Phenylephrine; Pyrilamine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Carbinoxamine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
Ceritinib: (Major) Avoid coadministration of tadalafil and ceritinib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of ceritinib for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as ceritinib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Chlophedianol; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Chlorpheniramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Clarithromycin: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clear
ance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Cobicistat: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4
Codeine; Phenylephrine; Promethazine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Conivaptan: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with conivaptan is necessary. Tadalafil is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A inhibitors would likely increase tadalafil exposure.
Crizotinib: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with crizotinib is necessary. Tadalafil is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Darunavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of darunavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of darunavir therapy. Stop tadalafil at least 24 hours prior to starting darunavir. After at least 1 week of darunavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and darunavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Darunavir; Cobicistat: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4 (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of darunavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of darunavir therapy. Stop tadalafil at least 24 hours prior to starting darunavir. After at least 1 week of darunavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and darunavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4 (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of darunavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of darunavir therapy. Stop tadalafil at least 24 hours prior to starting darunavir. After at least 1 week of darunavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and darunavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be n
oted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Delavirdine: (Major) Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving delavirdine. Coadministration of delavirdine with these drugs is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the ‘as needed’ dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the ‘once-daily’ dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. When used for pulmonary arterial hypertension, tadalafil should not be co-administered with potent CYP3A inhibitors.
Dexamethasone: (Minor) Tadalafil is metabolized principally by cytochrome P450 3A4. Studies have shown that concomitant administration of CYP3A4 enzyme-inducers, such as dexamethasone, will decrease plasma levels of tadalafil.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Dextromethorphan; Quinidine: (Moderate) Tadalafil is metabolized predominantly by the hepatic isoenzyme CYP3A4. Inhibitors of CYP3A4, such as quinidine, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
Diltiazem: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with diltiazem is necessary. Tadalafil is a CYP3A4 substrate and diltiazem is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Diphenhydramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Doxazosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Tadalafil is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
Duloxetine: (Moderate) Monitor blood pressure closely if duloxetine is coadministered with tadalafil due to the risk of additive hypotension. Orthostatic hypotension and syncope have been reported during duloxetine administration.
Dutasteride; Tamsulosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on tamsulosin therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of tamsulosin; increases in the alpha-blocker dose should be done in a stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue tamsulosin therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and tamsulosin.
Efavirenz: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
Elbasvir; Grazoprevir: (Moderate) Administering tadalafil with elbasvir; grazoprevir may result in elevated tadalafil plasma concentrations. Tadalafil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resume tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of tadalafil with cobicistat is expected to substantially increase the plasma concentrations of tadalafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used for pulmonary arterial hypertension (PAH) and the patient has been receiving cobicistat for at least 1 week, start tadalafil at 20 mg/day with an increase to 40 mg/day if tolerated. Avoid tadalafil during the initiation of cobicistat; it is recommended to stop tadalafil at least 24 hours prior to starting cobicistat. After the at least 1 week of cobicistat treatment, resum
e tadalafil at 20 mg daily with an increase to 40 mg daily based on tolerability. When used for erectile dysfunction, the manufacturer recommends a maximum tadalafil dose of 10 mg every 72 hours. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4
Enzalutamide: (Major) Avoid coadministration of tadalafil with enzalutamide in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of enzalutamide due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Erythromycin: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with erythromycin is necessary. Tadalafil is a CYP3A4 substrate and erythromycin is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking tadalafil. Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood pressure lowering effects may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with tadalafil can increase the potential for orthostatic signs and symptoms, including an increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil (10 mg or 20 mg) did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations.
Etravirine: (Moderate) Etravirine is an inducer of CYP3A4; coadministration may result in decreased tadalafil concentrations. Dosage adjustments may be needed based on clinical efficacy.
Fluconazole: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with fluconazole is necessary. Tadalafil is a CYP3A4 substrate and fluconazole is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Fluvoxamine: (Major) Avoid coadministration of fluvoxamine and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within a 72 hours of fluvoxamine for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as fluvoxamine, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Fosamprenavir: (Major) Monitor for an increase in tadalafil-related adverse reactions if coadministration with fosamprenavir is necessary. The prescribing information for fosamprenavir recommends to avoid coadministration of tadalafil for the treatment of pulmonary hypertension and to stop tadalafil at least 24 hours prior to starting fosamprenavir. After at least 1 week of fosamprenavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. For the treatment of erectile dysfunction, the prescribing information for fosamprenavir recommends to not exceed 10 mg tadalafil within 72 hours of fosamprenavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A inhibitors would likely increase tadalafil exposure.
Fosphenytoin: (Major) Avoid coadministration of tadalafil with fosphenytoin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of fosphenytoin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Grapefruit juice: (Moderate) Tadalafil is metabolized via the CYP3A4 isozyme. Grapefruit juice has been reported to decrease the metabolism of drugs metabolized via this enzyme. Grapefruit juice contains a compound that inhibits CYP3A4 in enterocytes in the GI tract. Tadalafil levels may increase; it is possible that tadalafil-induced side effects could also be increased in some individuals.
Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Hydralazine; Isosorbide Dinitrate, ISDN: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with tadalafil, a CYP3A substrate, as tadalafil toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Imatinib: (Major) Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as imatinib, STI-571, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the ‘as needed’ dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the ‘once-daily’ dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. When used for pulmonary arterial hypertension, tadalafil should not be co-administered with potent CYP3A inhibitors.
Indinavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of indinavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of indinavir therapy. Stop tadalafil at least 24 hours prior to starting indinavir. After at least 1 week of indinavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and indinavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection.
Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with tadalafil may result in increased serum concentrations of tadalafil. Tadalafil is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of tadalafil with rifampin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of rifampin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased tadalafil exposure by 88%.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of tadalafil with rifampin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of rifampin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased tadalafil exposure by 88%.
Isosorbide Dinitrate, ISDN: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Isosorbide Mononitrate: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Itraconazole: (Major) Avoid use of tadalafil for the treatment of pulmonary hypertension during and for 2 weeks after discontinuation of itraconazole treatment. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of itraconazole for the as needed dose or 2.5 mg daily for the once-daily dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as itraconazole, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Ketoconazole: (Major) Avoid coadministration of tadalafil and ketoconazole for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of ketoconazole for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Concurrent use may increase systemic exposure to tadalafil resulting in adverse effects including hypotension, syncope, visual changes, and prolonged erection. Tadalafil is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole 200 mg and 400 mg daily increased tadalafil AUC by 107% and 312%, respectively.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tadalafil; monitor for potential reduction in efficacy. Tadalafil is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of tadalafil; monitor for potential reduction in efficacy. Tadalafil is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Letermovir: (Moderate) An increase in the plasma concentration of tadalafil may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Avoid coadministration of tadalafil for pulmonary hypertension if the patient is receiving letermovir and cyclosporine. When used for erectile dysfunction in patients receiving letermovir with cyclosporine, the as needed (PRN) dose of tadalafil should not exceed 10 mg once every 72 hours and the daily dose should not exceed 2.5 mg. Tadalafil is predominately metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. In a drug interaction study, the exposure and maximum plasma concentration of tadalafil increased by up to 312% and 22%, respectively, when administered with another potent CYP3A4 inhibitor. Studies with moderate CYP3A4 inhibitors have not been conducted.
Levoketoconazole: (Major) Avoid coadministration of tadalafil and ketoconazole for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of ketoconazole for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Concurrent use may increase systemic exposure to tadalafil resulting in adverse effects including hypotension, syncope, visual changes, and prolonged erection. Tadalafil is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole 200 mg and 400 mg daily increased tadalafil AUC by 107% and 312%, respectively.
Lonafarnib: (Major) Avoid coadministration of tadalafil and lonafarnib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of lonafarnib for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as lonafarnib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Lopinavir; Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil
at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Lorcaserin: (Moderate) Lorcaserin is a serotonin 2C receptor agonist, and priapism is a potential effect of 5-HT2C receptor agonism. Because there is little experience with the combination of lorcaserin and medications indicated for erectile dysfunction (e.g., phosphodiesterase inhibitors), combined use should be approached with caution.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of tadalafil with lumacaftor; ivacaftor in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of lumacaftor; ivacaftor due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of tadalafil with lumacaftor; ivacaftor in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of lumacaftor; ivacaftor due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Mifepristone: (Major) Avoid coadministration of tadalafil and mifepristone for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of mifepristone for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as mifepristone, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Mitotane: (Major) Avoid coadministration of tadalafil with mitotane in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of mitotane due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Nefazodone: (Moderate) Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme and inhibitors of CYP3A4, such as nefazodone, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
Nelfinavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of nelfinavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of nelfinavir therapy. Stop tadalafil at least 24 hours prior to starting nelfinavir. After at least 1 week of nelfinavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and nelfinavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as tadalafil. The plasma concentrations of tadalafil can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Nevirapine: (Moderate) Monitor for reduced efficacy of tadalafil if coadministration with nevirapine is necessary; a dose adjustment may be needed. Concomitant use may decrease tadalafil exposure. Tadalafil is a CYP3A substrate and nevirapine is a weak CYP3A inducer.
Nifedipine: (Moderate) Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors). The patient should be monitored carefully and the dosage should be adjusted based on clinical response. For example, in patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 3 to 4 mmHg (age group 65 to 69 years) and 5 to 6 mmHg (age group 70 to 80 years) compared to placebo.
Nilotinib: (Moderate) Concomitant use of nilotinib, an moderate CYP3A4 inhibitor, and tadalafil, a CYP3A4 substrate, may result in increased tadalafil levels. A tadalafil dose reduction may be necessary if these drugs are used together.
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and tadalafil, when used for pulmonary hypertension, and consider an alternative COVID-19 therapy. Consider withholding tadalafil, when used for erectile dysfunction, during concomitant receipt of ritonavir-boosted nirmatrelvir. Coadministration may increase tadalafil exposure resulting in increased toxicity. Tadalafil is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Nitrates: (Contraindicated) Coadm
inistration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Nitroglycerin: (Contraindicated) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
Nitroprusside: (Contraindicated) Concomitant use of nitroprusside and tadalafil is contraindicated due to the risk of additive hypotension. If the patient has taken tadalafil, at least 48 hours must elapse before nitroprusside administration is considered; monitor hemodynamics closely. In addition, tadalafil may potentiate the nitric oxide-mediated platelet anti-aggregatory effect of nitroprusside.
Ombitasvir; Paritaprevir; Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Oritavancin: (Minor) Concomitant use of oritavancin and tadalafil may decrease the effectiveness of tadalafil; therefore, use caution and monitor therapeutic effects of tadalafil when coadministered. Oritavancin is a weak inducer of CYP3A4 and tadalafil is a CYP3A4 substrate. Clinical studies have shown that CYP3A4 inducers may reduce tadalafil exposure. The reduced exposure of tadalafil with the coadministration of CYP3A4 inducers can be anticipated to decrease the efficacy of tadalafil for once daily use; however the magnitude of decreased efficacy is unknown. Potent CYP3A4 inducers should be avoided with tadalafil when it is used to treat pulmonary hypertension.
Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and tadalafil, a CYP3A4 substrate, may cause an increase in systemic concentrations of tadalafil. Use caution when administering these drugs concomitantly.
Phenobarbital: (Major) Avoid coadministration of tadalafil with phenobarbital in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of phenobarbital due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of tadalafil with phenobarbital in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of phenobarbital due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Phenoxybenzamine: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
Phentolamine: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Phenytoin: (Major) Avoid coadministration of tadalafil with phenytoin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of phenytoin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Posaconazole: (Major) Posaconazole and tadalafil should be coadministered with caution due to an increased potential for tadalafil-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of tadalafil. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the ‘as needed’ dose should not exceed 10 mg within a 72 hour time period and the ‘once-daily’ dose should not exceed 2.5 mg.
Prazosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at
least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
Primidone: (Major) Avoid coadministration of tadalafil with primidone in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of primidone due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Promethazine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
Quinidine: (Moderate) Tadalafil is metabolized predominantly by the hepatic isoenzyme CYP3A4. Inhibitors of CYP3A4, such as quinidine, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension.
Ranolazine: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Inhibitors of CYP3A4 may reduce tadalafil clearance. In theory, CYP3A4 inhibitors which may interact with tadalafil include ranolazine. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the ‘as needed’ dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the ‘once-daily’ dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Ribociclib: (Major) Avoid coadministration of ribociclib and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ribociclib for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the tadalafil AUC after a 20-mg single dose by 312% and Cmax by 22%, relative to the values for tadalafil alone. The same strong inhibitor increased the tadalafil AUC after a 10-mg single dose by 107% and Cmax by 15%, relative to the values for tadalafil alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension, syncope, visual changes, and prolonged erection.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ribociclib for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the tadalafil AUC after a 20-mg single dose by 312% and Cmax by 22%, relative to the values for tadalafil alone. The same strong inhibitor increased the tadalafil AUC after a 10-mg single dose by 107% and Cmax by 15%, relative to the values for tadalafil alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension, syncope, visual changes, and prolonged erection.
Rifampin: (Major) Avoid coadministration of tadalafil with rifampin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of rifampin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased tadalafil exposure by 88%.
Rifapentine: (Major) Avoid coadministration of tadalafil with rifapentine in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of rifapentine due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Riociguat: (Contraindicated) Coadministration of riociguat and tadalafil is contraindicated due to the risk of hypotension. Do not administer riociguat 24 hours before or within 48 hours after tadalafil. Consider initiating riociguat at a starting dose of 0.5 mg in patients at risk of hypotension. Monitor for signs and symptoms of hypotension during transition of therapy.
Ritonavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Sapropterin: (Moderate) Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as phosphodiesterase inhibitors. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase (PDE5) inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not been studied in humans.
Saquinavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of saquinavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of saquinavir therapy. Stop tadalafil at least 24 hours prior to starting saquinavir. After at least 1 week of saquinavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and saquinavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recomme
nds the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Silodosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on silodosin therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of silodosin; increases in the alpha-blocker dose should be done in a stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue silodosin therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and silodosin.
Simeprevir: (Moderate) Coadministration of tadalafil with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in tadalafil plasma concentrations. No dose adjustments are required when treating erectile dysfunction. If treating pulmonary arterial hypertension, start at the lowest tadalafil dose and increase as needed while monitoring clinically.
St. John’s Wort, Hypericum perforatum: (Major) Avoid coadministration of tadalafil with St. John’s wort in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of St. John’s wort due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and St. John’s wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Tamsulosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on tamsulosin therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of tamsulosin; increases in the alpha-blocker dose should be done in a stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue tamsulosin therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and tamsulosin.
Telithromycin: (Major) Avoid coadministration of telithromycin and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within a 72-hours of telithromycin for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as telithromycin may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Terazosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest recommended dose of tadalafil. Conversely, patients already receiving an optimized dose of tadalafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in stepwise fashion. When tadalafil is used for benign prostatic hypertrophy (BPH), discontinue alpha-blocker therapy at least 1 day prior to initiating tadalafil therapy. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of tadalafil and an alpha-blocker.
Tipranavir: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of tipranavir for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of tipranavir therapy. Stop tadalafil at least 24 hours prior to starting tipranavir. After at least 1 week of tipranavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and tipranavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Trandolapril; Verapamil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with verapamil is necessary. Tadalafil is a CYP3A4 substrate and verapamil is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Tucatinib: (Major) Avoid coadministration of tadalafil and tucatinib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of tucatinib for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as tucatinib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Vardenafil: (Major) Avoid coadministration of tadalafil and vardenafil. The safety and efficacy of combinations of tadalafil and other phosphodiesterase 5 (PDE5) inhibitors, such as vardenafil, has not been studied.
Vemurafenib: (Minor) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as tadalafil, could be expected with concurrent use. Use caution, and monitor therapeutic effects of tadalafil when coadministered with vemurafenib.
Verapamil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with verapamil is necessary. Tadalafil is a CYP3A4 substrate and verapamil is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Vericiguat: (Major) Coadministration of vericiguat and phosphodiesterase type 5 (PDE5) inhibitors is not recommended due to the risk of hypotension. The manufacturer of avanafil contraindicates this combination. Limited data are available on the concurrent use of vericiguat and PDE5 inhibitors in patients with heart failure.
Vigabatrin: (Major) Vigabatrin should not be used with phosphodiesterase inhibitors, which is associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of tadalafil and clarithromycin for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of clarithromycin for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is metabolized predominantly by CYP3A4. Potent in
hibitors of CYP3A4, such as clarithromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Voriconazole: (Major) Avoid coadministration of voriconazole and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of voriconazole for the ‘as needed’ dose or 2.5 mg daily for the ‘once-daily’ dose. Tadalafil is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the tadalafil AUC after a 20-mg single dose by 312% and Cmax by 22%, relative to the values for tadalafil alone. The same strong inhibitor increased the tadalafil AUC after a 10-mg single dose by 107% and Cmax by 15%, relative to the values for tadalafil alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension, syncope, visual changes, and prolonged erection.
Voxelotor: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with voxelotor is necessary. Tadalafil is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A inhibitors would likely increase tadalafil exposure.

Pregnancy and Lactation

Mechanism of Action

Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased concentrations of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. PDE5 is responsible for degradation of cGMP in the corpus cavernosum. Tadalafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Tadalafil has no direct relaxant effect on isolated human corpus cavernosum, and at recommended doses, does not affect in the absence of sexual stimulation. In vitro studies show that tadalafil is selective for PDE5 and is more than 10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is more than 10,000-fold more potent for PDE5 than for PDE3 found in the heart and blood vessels. Also, tadalafil has 700-fold greater selectivity for PDE5 vs. PDE6, an enzyme found in the retina and involved in phototransduction. Compare this selectivity to the selectivity of sildenafil which has only a 10-fold selectivity for PDE5 vs. PDE6. This lower selectivity of sildenafil for PDE5 vs. PDE6 is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of sildenafil. Further, tadalafil is more than 9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4. PDE11 is an enzyme found in human skeletal muscle, prostate, testes, and other tissues. Inhibition of human recombinant PDE11A1, and to a lesser extent, PDE11A4 activities occur at tadalafil concentrations within the therapeutic range. The physiological role and clinical effects of PDE11 inhibition in humans have not been elucidated.

The mechanism by which tadalafil reduces the symptoms of benign prostatic hyperplasia (BPH) has not been established; however, the effect of PDE5 inhibition on cGMP concentrations in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, bladder, and their vascular supply.[28220]

Tadalafil can inhibit PDE5 present in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in the relaxation of pulmonary vascular smooth muscle and subsequent pulmonary vasodilation, thereby making tadalafil an effective agent in treating pulmonary hypertension.[40259]

Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Dyspepsia is one of the most common adverse reactions associated with PDE5 inhibitor therapy.

Pharmacokinetics

Tadalafil is administered orally. The pharmacokinetics of tadalafil were evaluated in healthy young volunteers. Once absorbed, tadalafil is distributed into the tissues and has a volume of distribution of 63 to 77 L. Protein binding is 94% at therapeutic concentrations. Less than 0.0005% of the administered dose appeared in the semen of healthy subjects. The primary route of elimination for tadalafil is via the hepatic cytochrome P450 isoenzyme CYP3A4, which metabolizes the drug to a catechol metabolite. The catechol metabolite undergoes extensive methylation to form the methylcatechol metabolite and then glucuronidation to the form the methylcatechol glucuronide conjugate. The major circulating metabolite is the methylcatechol glucuronide, which is 13,000 times less potent for PDE5 than tadalafil. Methylcatechol concentrations are less than 10% of glucuronide concentrations. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose). The mean elimination half-life is 15 to 17.5 hours in healthy subjects.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
Tadalafil is a CYP3A4 substrate. Avoidance of use with potent CYP3A4 inhibitors or inducers is recommended.

The pharmacokinetics of tadalafil were evaluated in healthy young volunteers. After a single oral dose, the maximum observed plasma concentration (Cmax) occurs between 30 minutes and 8 hours (Tmax median time of 2 to 4 hours). The AUC increased proportionately over a dose range of 2.5 mg to 20 mg. In individuals with pulmonary arterial hypertension (PAH) administered 20 mg and 40 mg tadalafil, an approximately 50% greater increase in AUC was observed indicating a less than proportional increase in exposure over the dose range of 2.5 mg to 40 mg. Following daily administration of tadalafil 20 mg and 40 mg to patients with PAH, steady-state concentrations were attained within 5 days and exposure was approximately 30% higher than after a single dose. The usual onset of action is within 30 to 45 minutes, and the usual duration is up to 36 hours. In patients with pulmonary arterial hypertension, the mean oral clearance was 1.6 L/hour (versus 3.4 L/ hour in healthy individuals) and the mean terminal half-life was 35 hours. The average tadalafil exposure at steady-state following 40 mg was 26% higher in patients with PAH compared to healthy patients, suggesting reduced clearance in individuals with PAH. Food does not affect the pharmacokinetics of tadalafil; however, absolute bioavailability data are not available.

Label: TADALAFIL tablet, film coated

These highlights do not include all the information needed to use TADALAFIL TABLETS safely and effectively. See full prescribing information for TADALAFIL TABLETS.

TADALAFIL tablets, for oral administration
Initial U.S. Approval: 2003

INDICATIONS AND USAGE

Tadalafil tablets are a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class II – III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%). (1.1)

DOSAGE AND ADMINISTRATION

40 mg once daily, with or without food. (2.1)
Dividing the dose (40 mg) over the course of the day is not recommended. (2.1)
Use with ritonavir requires dosage adjustments. (2.4)

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

Concomitant organic nitrates (4.1)
Concomitant Guanylate Cyclase (GC) Stimulators (4.2)
History of known serious hypersensitivity reaction to tadalafil or CIALIS. (4.3)

WARNINGS AND PRECAUTIONS

Hypotension: Carefully consider whether patients with certain underlying cardiovascular disease, could be adversely affected by vasodilatory effects of tadalafil. Not recommended in patients with pulmonary veno-occlusive disease. (5.1, 5.2)
Effects on the eye: Sudden loss of vision could be a sign of non-arteritic ischemic optic neuropathy (NAION) and may be permanent. (5.3)
Hearing impairment: Cases of sudden decrease or loss of hearing have been reported with CIALIS. (5.4)
Concomitant PDE5 inhibitors: Avoid use with CIALIS or other PDE5 inhibitors. (5.5)
Prolonged erection: Advise patients to seek emergency treatment if an erection lasts >4 hours. (5.6)

ADVERSE REACTIONS

The most common adverse reaction is headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Pulmonary Arterial Hypertension

2 DOSAGE AND ADMINISTRATION

2.1 Pulmonary Arterial Hypertension

2.2 Dose Adjustment in Renal Impairment

2.3 Dose Adjustment in Hepatic Impairment

2.4 Dose Adjustments for Use with Ritonavir

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Concomitant Organic Nitrates

4.2 Concomitant Guanylate Cyclase (GC) Stimulators

4.3 Hypersensitivity Reactions

5 WARNINGS AND PRECAUTIONS

5.1 Hypotension

5.2 Worsening Pulmonary Vascular Occlusive Disease

5.3 Visual Loss

5.4 Hearing Impairment

5.5 Combination with Other PDE5 Inhibitors

5.6 Prolonged Erection

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Nitrates

7.2 Alpha-Blockers

7.3 Antihypertensives

7.4 Alcohol

7.5 CYP3A Inhibitors/Inducers

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Tadalafil for Pulmonary Arterial Hypertension

14.2 Long-Term Treatment of Pulmonary Arterial Hypertension

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage

17 PATIENT COUNSELING INFORMATION

1.1 Pulmonary Arterial Hypertension

Tadalafil tablets are indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class II – III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%).

2.1 Pulmonary Arterial Hypertension

The recommended dose of tadalafil tablets is 40 mg (two 20 mg tablets) taken once daily with or without food. Dividing the dose (40 mg) over the course of the day is not recommended.

2.2 Dose Adjustment in Renal Impairment

Mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min): Start dosing at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Severe (creatinine clearance

2.3 Dose Adjustment in Hepatic Impairment

Mild or moderate (Child Pugh Class A or B): Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis, consider a starting dose of 20 mg once per day. Severe (Child Pugh Class C): Patients with severe hepatic cirrhosis have not been studied. Avoid use of tadalafil tablets [see Use in Specific Populations (8.7)] .

2.4 Dose Adjustments for Use with Ritonavir

Co-administration of Tadalafil Tablets in Patients on Ritonavir In patients receiving ritonavir for at least one week, start tadalafil tablets at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)] . Co-administration of Ritonavir in Patients on Tadalafil Tablets Avoid use of tadalafil tablets during the initiation of ritonavir. Stop tadalafil tablets at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume tadalafil tablets at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)] .

Tadalafil Tablets USP, 20 mg are orange colored, round shaped, biconvex film coated tablets debossed with ‘L 124’ on one side and plain on other side.

4.1 Concomitant Organic Nitrates

Tadalafil is contraindicated in patients who are using any form of organic nitrate, either regularly or intermittently. Do not use nitrates within 48 hours of the last dose of Tadalafil. Tadalafil potentiates the hypotensive effect of nitrates. This potentiation is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway [see Clinical Pharmacology (12.2)] .

4.2 Concomitant Guanylate Cyclase (GC) Stimulators

Coadministration of GC stimulators such as riociguat with Tadalafil is contraindicated. Tadalafil may potentiate the hypotensive effects of GC stimulators.

4.3 Hypersensitivity Reactions

Tadalafil is contraindicated in patients with a known serious hypersensitivity to tadalafil or CIALIS. Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis [see Adverse Reactions (6.2)] .

5.1 Hypotension

Tadalafil has vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing tadalafil, carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with preexisting hypotension, with autonomic dysfunction, with left ventricular outflow obstruction, may be particularly sensitive to the actions of vasodilators.

5.2 Worsening Pulmonary Vascular Occlusive Disease

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. Should signs of pulmonary edema occur when tadalafil is administered, the possibility of associated PVOD should be considered.

5.3 Visual Loss

When used to treat erectile dysfunction, non–arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including tadalafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥50 in the general population. An observational casecrossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, typical of erectile dysfunction treatment, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.

5.4 Hearing Impairment

Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in patients taking tadalafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions (6.2)] .

5.5 Combination with Other PDE5 Inhibitors

Tadalafil is also marketed for erectile dysfunction. The safety and efficacy of taking tadalafil together with another PDE5 inhibitor has not been studied. Inform patients taking tadalafil not to take other PDE5 inhibitors.

5.6 Prolonged Erection

There have been reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Patients with conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) are at an increased risk. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention.

Hypotension [see Warnings and Precautions (5.1)]
Visual Loss [see Warnings and Precautions (5.3) and Patient Counseling Information (17)]
Hearing loss [see Warnings and Precautions (5.4)]
Priapism [see Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience

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

Tadalafil was administered to 398 patients with PAH during clinical trials worldwide. In trials of tadalafil, a total of 311 and 251 subjects have been treated for at least 182 days and 360 days, respectively. The overall rates of discontinuation because of an adverse event (AE) in the placebo-controlled trial were 9% for tadalafil 40 mg and 15% for placebo. The rates of discontinuation because of AEs, other than those related to worsening of PAH, in patients treated with tadalafil 40 mg was 4% compared to 5% in placebo-treated patients.

In the placebo-controlled study, the most common AEs were generally transient and mild to moderate in intensity.

Table 1 presents treatment-emergent adverse events reported by ≥9% of patients in the tadalafil 40 mg group and occurring more frequently than with placebo.

$Table 1: Treatment-Emergent Adverse Events Reported by ≥9% of Patients in Tadalafil and More Frequent than Placebo by 2%

EVENT	Placebo (%) (N=82)	Tadalafil 20 mg (%) (N=82)	Tadalafil 40 mg (%) (N=79)
Headache	15	32	42
Myalgia	4	9	14
Nasopharyngitis	7	2	13
Flushing	2	6	13
Respiratory Tract Infection (Upper and Lower)	6	7	13
Pain in Extremity	2	5	11
Nausea	6	10	11
Back Pain	6	12	10
Dyspepsia	2	13	10
Nasal Congestion (Including sinus congestion)	1	0	9

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of tadalafil. These events have been chosen for inclusion either because of their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. The list does not include adverse events that are reported from clinical trials and that are listed elsewhere in this section.

Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in temporal association with the use of tadalafil [see Contraindications (4.1)]. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of tadalafil without sexual activity. Others were reported to have occurred hours to days after the use of tadalafil and sexual activity. It is not possible to determine whether these events are related directly to tadalafil, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors.

Hypersensitivity reactions including urticaria, Stevens–Johnson syndrome, and exfoliative dermatitis

Migraine, seizure and seizure recurrence, and transient global amnesia

Visual field defect, retinal vein occlusion, retinal artery occlusion, and NAION [see Warnings and Precautions (5.3) and Patient Counseling Information (17)].

Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of tadalafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors [see Warnings and Precautions (5.4) and Patient Counseling Information (17)] .

7.1 Nitrates

Administration of nitrates within 48 hours after the last dose of tadalafil is contraindicated [see Contraindications (4.1)] .

7.2 Alpha-Blockers

PDE5 inhibitors, including tadalafil, and alpha–adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin, alfuzosin or tamsulosin [see Clinical Pharmacology (12.2)] .

7.3 Antihypertensives

PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood–pressure– lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo [see Clinical Pharmacology (12.2)] .

7.4 Alcohol

Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood pressure–lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil (10 mg or 20 mg) did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations. [See Clinical Pharmacology (12.2)] .

7.5 CYP3A Inhibitors/Inducers

Ritonavir Ritonavir initially inhibits and later induces CYP3A, the enzyme involved in the metabolism of tadalafil. At steady state of ritonavir (about 1 week), the exposure to tadalafil is similar as in the absence of ritonavir [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)] . Potent Inhibitors of CYP3A Tadalafil is metabolized predominantly by CYP3A in the liver. In patients taking potent inhibitors of CYP3A such as ketoconazole, and itraconazole, avoid use of tadalafil [see Clinical Pharmacology (12.3)] . Potent Inducers of CYP3A For patients chronically taking potent inducers of CYP3A, such as rifampin, avoid use of tadalafil [see Clinical Pharmacology (12.3)] .

8.1 Pregnancy

Risk Summary Limited data from case series with tadalafil use in pregnant women have not identified a drugassociated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats or mice during organogenesis at exposures 7 times the exposure at the maximum recommended human dose (MRHD) of 40 mg/day based on AUC (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats. Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at unbound tadalafil exposures up to 7 times the exposure at the maximum recommended human dose (MRHD) of 40 mg/day during organogenesis based on AUC. In one of two perinatal/postnatal developmental studies in rats, a reduction of postnatal pup survival was observed at dose levels of 60, 200 and 1000 mg/kg. The no-observed- effect-level (NOEL) for developmental toxicity was 30 mg/kg, which provided maternal exposure to unbound tadalafil concentrations approximately 5 times the exposure at the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 200 mg/kg/day, which produced AUCs greater than 8 times the exposure at the MRHD. Surviving offspring had normal development and reproductive performance

8.2 Lactation

Risk Summary There are no data on the presence of tadalafil and/or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Tadalafil and/or its metabolites are present in the milk of lactating rats at concentrations approximately 2.4-times that found in the plasma. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tadalafil and any potential adverse effects on the breastfed child from tadalafil or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Infertility Males Based on the data from 3 studies in adult males, tadalafil decreased sperm concentrations in the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. There was no adverse effect of tadalafil 10 mg or 20 mg on mean concentrations of testosterone, luteinizing hormone or follicle stimulating hormone. The clinical significance of the decreased sperm concentrations in the two studies is unknown. There have been no studies evaluating the effect of tadalafil on fertility in men or women [see Clinical Pharmacology (12.2)] .

8.4 Pediatric Use

8.5 Geriatric Use

Of the total number of subjects in the clinical study of tadalafil for pulmonary arterial hypertension, 28 percent were 65 and over, while 8 percent were 75 and over. No overall differences in safety were observed between subjects over 65 years of age compared to younger subjects or those over 75 years of age. No dose adjustment is warranted based on age alone; however, a greater sensitivity to medications in some older individuals should be considered. [See Dosage and Administration (2.2) and Clinical Pharmacology (12.3)] .

8.6 Renal Impairment

For patients with mild or moderate renal impairment, start tadalafil at 20 mg once daily. Increase the dose to 40 mg once daily based upon individual tolerability [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)] . In patients with severe renal impairment, avoid use of tadalafil because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see Clinical Pharmacology (12.3)] .

8.7 Hepatic Impairment

Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A or B), consider a starting dose of tadalafil 20 mg once daily. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied, thus avoid use of tadalafil in such patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)] .

Single doses up to 500 mg have been given to healthy male subjects, and multiple daily doses up to 100 mg have been given to male patients with erectile dysfunction. Adverse reactions were similar to those seen at lower doses. Doses greater than 40 mg have not been studied in patients with pulmonary arterial hypertension. In cases of overdose, standard supportive measures should be adopted as needed. Hemodialysis contributes negligibly to tadalafil elimination.

Tadalafil Tablets USP, an oral treatment for pulmonary arterial hypertension, is a selective inhibitor of cyclic guanosine monophosphate (cGMP)–specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C 22 H 19 N 3 O 4 representing a molecular weight of 389.41. The structural formula is:

The chemical designation is pyrazino[1´,2´:1,6]pyrido[3,4–b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl) 2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-. It is a crystalline solid that is freely soluble in dimethylsulfoxide, slightly soluble in methylene chloride and practically insoluble in water. Tadalafil Tablets USP are available as orange colored, round shaped, biconvex film coated tablets debossed with ‘L 124’ on one side and plain on other side for oral administration. Each tablet contains 20 mg of tadalafil and the following inactive ingredients: croscarmellose sodium, hypromellose, iron oxide yellow, iron oxide red, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulphate, talc, titanium dioxide, and triacetin.

12.1 Mechanism of Action

Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations in the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed. Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in pulmonary vascular smooth muscle, visceral smooth muscle, corpus cavernosum, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas. In vitro studies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. These studies have shown that tadalafil is >10,000–fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is >10,000–fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700–fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadalafil is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14–fold more potent for PDE5 than for PDE11A1 and 40–fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues. In vitro , tadalafil inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.

12.2 Pharmacodynamics

Effects on Blood Pressure When Administered with Nitrates In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Do not use tadalafil in patients taking any form of nitrates [see Contraindications (4.1)] . A double–blind, placebo–controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) assessed the interaction between nitroglycerin and tadalafil. Subjects received daily doses of tadalafil 20 mg or matching placebo for 7 days and then were given a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre–specified timepoints following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). A significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although a few more tadalafil subjects compared to placebo experienced greater blood–pressure lowering effects at this timepoint. After 48 hours, the interaction was not detectable. [See Contraindications (4.1)] . Effects on Blood Pressure The effects of tadalafil on blood pressure alone and administered with antihypertensives, alcohol, and alpha-blockers is shown in Figure 1.

a In some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed, and dizziness occurred at a similar frequency to alcohol alone. b In studies of tadalafil co-administration with doxazosin, the number of subjects with potentially clinically significant standing blood pressure decreases was greater for the combination. Some patients had symptoms associated with the decrease in blood pressure including syncope. Figure 1: Effects of Tadalafil on Blood Pressure Effects on Cardiac Electrophysiology The effect of a single 100 mg dose of tadalafil (2.5 times the recommended dose) on the QT interval was evaluated at the time of peak tadalafil concentration in a randomized, double– blinded, placebo, and active–controlled (intravenous ibutilide) crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two–sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two–sided 90% CI=1.2, 4.4). In this study, the mean increase in heart rate associated with a 100 mg dose of tadalafil compared to placebo was 3.1 beats per minute. Effects on Exercise Stress Testing The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise–induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was similar to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post– exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by tadalafil of the blood–pressure–lowering effects of nitrates. Effects on Vision Single oral doses of PDE inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth–Munsell 100–hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (

12.3 Pharmacokinetics

Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. In PAH patients administered between 20 and 40 mg of tadalafil, an approximately 1.5-fold greater AUC was observed indicating a less than proportional increase in exposure over the entire dose range of 2.5 to 40 mg. During tadalafil 20 and 40 mg once daily dosing, steady-state plasma concentrations were attained within 5 days, and exposure was approximately 1.3-fold higher than after a single dose. Absorption After single oral-dose administration, the maximum observed plasma concentration (C max ) of tadalafil is achieved between 2 and 8 hours (median time of 4 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined. The rate and extent of absorption of tadalafil are not influenced by food; thus tadalafil may be taken with or without food. Distribution The mean apparent volume of distribution following oral administration is approximately 77 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Metabolism Tadalafil is predominantly metabolized by CYP3A to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations. Elimination Following 40 mg, the mean oral clearance for tadalafil is 3.4 L/hr and the mean terminal half-life is 15 hours in healthy subjects. In patients with pulmonary hypertension not receiving concomitant bosentan, the mean oral clearance for tadalafil is 1.6 L/hr, and the mean terminal half-life is 35 hours. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose). Population pharmacokinetics In patients with pulmonary hypertension not receiving concomitant bosentan, the average tadalafil exposure at steady-state following 40 mg was 26% higher when compared to those of healthy volunteers. The results suggest a lower clearance of tadalafil in patients with pulmonary hypertension compared to healthy volunteers. Geriatric patients In healthy male elderly subjects (65 years or over) after a 10 mg dose, a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) with no effect on C max was observed relative to that in healthy subjects 19 to 45 years of age. Renal impairment In clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal impairment. In subjects with end-stage renal disease on hemodialysis, there was a two-fold increase in C max and 2.7- to 4.1-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil, respectively. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in subjects with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to tadalafil or metabolite elimination [see Dosage and Administration (2.2)] . Hepatic impairment In clinical pharmacology studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) was comparable to exposure in healthy subjects when a dose of 10 mg was administered. There are no available data for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C) [see Dosage and Administration (2.3)] . Patients with diabetes mellitus In male patients with diabetes mellitus after a 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and C max was 5% lower than that observed in healthy subjects. No dose adjustment is warranted. Race Pharmacokinetic studies have included subjects from different ethnic groups, and no differences in the typical exposure to tadalafil have been identified. No dose adjustment is warranted. Gender In healthy female and male subjects following single and multiple-doses of tadalafil, no clinically relevant differences in exposure (AUC and C max ) were observed. No dose adjustment is warranted. Drug interaction studies Tadalafil is a substrate of and predominantly metabolized by CYP3A. Cytochrome P450 3A4 inhibitors Ketoconazole increased tadalafil exposure relative to the values for tadalafil alone (Figure 2). Although specific interactions have not been studied, other CYP3A inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure. Ritonavir Ritonavir increased tadalafil 20–mg single-dose exposure relative to the values for tadalafil alone. Ritonavir inhibits and induces CYP3A, the enzyme involved in the metabolism of tadalafil, in a time-dependent manner. The initial inhibitory effect of ritonavir on CYP3A may be mitigated by a more slowly evolving induction effect so that after about 1 week of ritonavir twice daily, the exposure of tadalafil is similar in the presence of and absence of ritonavir [see Dosage and Administration (2.4) and Drug Interactions (7.5)] . Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure. Cytochrome P450 3A4 inducers Rifampin (600 mg daily), a CYP3A inducer, reduced tadalafil 10 mg single– dose exposure (AUC) by 88% and Cmax by 46%, relative to the values for tadalafil 10 mg alone [see Drug Interactions (7.5)] . Bosentan, a substrate of CYP2C9 and CYP3A and a moderate inducer of CYP3A, CYP2C9 and possibly CYP2C19, reduced tadalafil systemic exposure following multiple-dose coadministration (Figure 2). Although specific interactions have not been studied, other CYP3A inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure. Exposure changes of tadalafil following co-administration with other drugs are shown in Figure 2

a Ritonavir is also a CYP2C9/CYP2C19/CYP2D6 Inhibitor and CYP3A inducer. b [see Dosage and Administration (2.4) ]. c Bosentan is also a CYP2C9/CYP2C19 inducer. Figure 2: Impact of Other Drugs on the Pharmacokinetics of Tadalafil Cytochrome P450 substrates Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Exposure changes of drugs following co-administration with tadalafil are shown in Figure 3.

a A small augmentation (increase of 3 beats per minute) in heart rate was observed with theophylline. b Tadalafil (40 mg qd) had no clinically significant effect on exposure (AUC and Cmax) of bosentan metabolites. c 95% CI Figure 3: Impact of Tadalafil on the Pharmacokinetics of Other Drugs

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis Tadalafil was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound tadalafil, were approximately 5–fold for mice, and 7– and 14–fold for male and female rats, respectively, the exposures at the maximum recommended human dose (MRHD) of 40 mg. Mutagenesis Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Tadalafil was not clastogenic in the in vitro chromosomal aberration test Page 18 of 26 in human lymphocytes or the in vivo rat micronucleus assays. Impairment of Fertility There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg/kg/day, a dose producing AUCs for unbound tadalafil of 6–fold for males or 17–fold for females the exposures at the MRHD of 40 mg. In beagle dogs given tadalafil daily for 3 to 12 months, there was treatment–related non–reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20 to 100% of the dogs that resulted in a decrease in spermatogenesis in 40 to 75% of the dogs at doses of ≥10 mg/kg/day. Systemic exposure (based on AUC) at no–observed–adverse-effect–level (NOAEL) (10 mg/kg/day) for unbound tadalafil was similar to that expected in humans at the MRHD of 40 mg. There were no treatment–related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years.

13.2 Animal Toxicology and/or Pharmacology

Animal studies showed vascular inflammation in tadalafil–treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound tadalafil exposure of 1– to 17–fold the human exposure (AUCs) at the MRHD of 40 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1– and 6-month studies at unbound tadalafil exposure of 0.5– to 38–fold the human exposure (AUC) at the MRHD of 40 mg. In a 12–month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 4– to 10–fold the human exposure at the MRHD of 40 mg. The abnormal blood–cell findings were reversible within 2 weeks upon removal of the drug.

14.1 Tadalafil for Pulmonary Arterial Hypertension

A randomized, double-blind, 16 week placebo-controlled study was conducted in 405 patients with pulmonary arterial hypertension, defined as a resting mean pulmonary artery pressure (mPAP) ≥25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤15 mm Hg, and pulmonary vascular resistance (PVR) ≥3 Wood units via right heart catheterization. Allowed background therapy included bosentan (maintenance dosing up to 125 mg twice daily) and chronic anticoagulation. The use of prostacyclin or analogue, L–arginine, phosphodiesterase inhibitor, or other chronic PAH medications were not permitted. Subjects were randomly assigned to 1 of 5 treatment groups (tadalafil 2.5, 10, 20, 40 mg, or placebo) in a 1:1:1:1:1 ratio. Subjects had to be at least 12 years of age and had a diagnosis of PAH that was idiopathic, heritable, related to connective tissue disease, anorexigen use, human immunodeficiency virus (HIV) infection, associated with an atrial-septal defect, or associated with surgical repair of a congenital systemic-to-pulmonary shunt of least 1 year in duration (for example, ventricular septal defect, patent ductus arteriosus). Patients with a history of left-sided heart disease, severe renal insufficiency, or pulmonary hypertension related to conditions other than specified in the inclusion criteria were not eligible for enrollment. The mean age of all subjects was 54 years (range 14 to 90 years) with the majority of subjects being Caucasian (81%) and female (78%). PAH etiologies were predominantly idiopathic or heritable PAH (61%) and related to connective tissue disease (23%). More than half (53%) of the subjects in the study were receiving concomitant bosentan therapy. The majority of subjects had a World Health Organization (WHO) Functional Class III (65%) or II (32%). The mean baseline 6 minute walk distance (6-MWD) was 343 meters. Of the 405 subjects, 341 completed the study. The primary efficacy endpoint was the change from baseline at week 16 in 6-MWD ( see Figure 4). In the tadalafil 40 mg treatment group, the placebo-adjusted mean change increase in 6-MWD was 33 meters (95% C.I. 15 to 50 meters; p=0.0004). The improvement in 6-MWD was apparent at 8 weeks of treatment and then maintained at week 12 and week 16.

Figure 4: 6-Minute Walk Distance (meters) Mean Change from Baseline, with 95% Confidence Intervals Placebo-adjusted changes in 6-MWD at 16 weeks were evaluated in subgroups ( see Figure 5). In patients taking only tadalafil 40 mg (i.e., without concomitant bosentan), the placebo-adjusted mean change in 6-MWD was 44 meters. In patients taking tadalafil 40 mg and concomitant bosentan therapy, the placebo adjusted mean change in 6-MWD was 23 meters.

Figure 5: Placebo-adjusted Mean Change in 6-Minute Walk Distance (meters) of Tadalafil 40 mg, with 95% Confidence Intervals There was less clinical worsening (defined as death, lung transplantation, atrial septostomy, hospitalization because of worsening PAH, initiation of new PAH therapy [prostacyclin or analog, endothelin receptor antagonist, PDE5 inhibitor], or worsening WHO functional class) in the tadalafil 40 mg group compared to the placebo group and the groups that used lower doses of tadalafil.

Table 2: Number (percent) with Clinical Worsening a

a Subjects may be counted in more than one category
		Tadalafil
	Placebo N = 82	2 . 5 mg N = 82	10 mg N = 80	20 mg N = 82	40 mg N = 79
Total with clinical worsening	13 (16)	10 (12)	7 (9)	8 (10)	4 (5)
Death	1	0	1	0	0
Hospitalization for worsening PAH	2	2	3	0	1
New PAH therapy	0	1	0	2	1
Worsening WHO class	11	10	6	6	3

14.2 Long-Term Treatment of Pulmonary Arterial Hypertension

Patients (N=357) from the placebo-controlled study entered a long-term extension study. Of these, 311 patients have been treated with tadalafil for at least 6 months and 182 for 1 year (median exposure 356 days; range 2 days to 415 days). The survival rate in the extension study was 96.5 per 100 patient years. Without a control group, these data must be interpreted cautiously.

16.1 How Supplied

Tadalafil Tablets USP are supplied as follows: 20 mg orange colored, round shaped, biconvex film coated tablets debossed with ‘L 124’ on one side and plain on other side. Bottles of 30 NDC 68180-914-06 Bottles of 60 NDC 68180-914-07

16.2 Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep out of reach of children.

Inform patients of contraindication of tadalafil with any use of organic nitrates or GC stimulators.
Inform patients that tadalafil is also marketed as CIALIS for erectile dysfunction (ED) and for the signs and symptoms of benign prostatic hyperplasia (BPH). Advise patients taking tadalafil not to take CIALIS or other PDE5 inhibitors.
Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking tadalafil. Such an event may be a sign of NAION. Also discuss with patients that there is an increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors.
Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking tadalafil. These events may be accompanied by tinnitus and dizziness.

The brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products.

Medicines that treat chest pain (angina)
Nitroglycerin in any form including tablets, patches, sprays, and ointments
Other nitrate medicines (isosorbide mononitrate or dinitrate)
Street drugs that are inhaled, called “poppers” (amyl nitrate, butyl nitrate or nitrite)

Ask your healthcare provider or pharmacist if you are not sure if you take a nitrate or guanylate cyclase stimulator medicine.

Tadalafil tablets are a prescription medicine used to treat pulmonary arterial hypertension (PAH, high blood pressure in your lungs) to improve your ability to exercise.

It is not known if tadalafil tablets are safe or effective in children.

take any medicines called nitrates.
use recreational drugs called “poppers” like amyl nitrate, butyl nitrate or nitrite.
take any medicines called guanylate cyclase stimulators
are allergic to tadalafil or any other ingredient in tadalafil tablets. See “What are the ingredients in tadalafil tablets?” at the end of this leaflet.

See “What is the most important information I should know about tadalafil tablets?”

What should I tell my healthcare provider before taking tadalafil tablets?

Before taking tadalafil tablets, tell your healthcare provider about all of your medical conditions, including if you:

are allergic to tadalafil tablets or CIALIS or any of its ingredients. See the end of this leaflet for a complete list of ingredients in tadalafil tablets.
have pulmonary veno-occlusive disease (PVOD)
have heart problems
have low blood pressure
have liver problems
have kidney problems or get dialysis
have retinitis pigmentosa, a rare genetic eye disease
have ever had any sudden vision loss, including any damage to your optic nerve or NAION.
have ever had hearing problems such as ringing in the ears, dizziness, or loss of hearing
have a deformed penis shape or Peyronie’s disease
have had an erection that lasted more than 4 hours
have blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia
are pregnant or planning to become pregnant. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
are breastfeeding or plan to breast feed. If you breastfeed while taking tadalafil tablets, it is likely that tadalafil tablets will pass into your breast milk. You and your healthcare provider should decide if you will take tadalafil tablets or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Tadalafil tablets and other medicines may affect each other.

Especially tell your healthcare provider if you take any of these medicines:

nitrates or guanylate cyclase stimulators (see “What is the most important information I should know about tadalafil tablets?” )
alpha blockers, used to treat prostate disease and high blood pressure. Your blood pressure could suddenly drop. You could get dizzy or faint.
protease inhibitors, used to treat HIV infection, such as ritonavir (Norvir ® , Kaletra ® )
ketoconazole (Extina ® , Xolegel ® , Ketozole ® , Nizoral A-D ® , Nizoral ® ) itraconazole (Sporanox ® )
erythromycin (several brand names exist. Please consult your healthcare provider to determine if you are taking this medicine)
rifampin (Rifadin ® , Rifamate ® , Rifater ® , Rimactane ® )
bosentan (Tracleer ® )
phenobarbital, phenytoin (Dilantin ® ), carbamazepine (Tegretol ® )
CIALIS ® or other medicines or treatments for erectile dysfunction (impotence).
Tadalafil tablets are also marketed as CIALIS for the treatment of male erectile dysfunction (ED, impotence) and for the signs and symptoms of benign prostatic hyperplasia (BPH, enlarged prostate). Do not take both tadalafil tablets and CIALIS. Do not take tadalafil tablets and other medicines or treatments for erectile dysfunction.

Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

Take tadalafil tablets exactly as your healthcare provider tells you.
Take tadalafil tablets at the same time every day. You should take both tablets at the same time, one after the other, every day. Do not split your dose.
Tadalafil tablets can be taken with or without food.
Do not change your dose or stop taking tadalafil tablets without speaking to your healthcare provider.
If you take too much tadalafil tablets, call your healthcare provider or go to an emergency department right away.

What should I avoid while taking tadalafil tablets?

Do not have more than 4 alcohol-containing drinks in a short period of time while you take tadalafil tablets. Drinking too much alcohol can lower your blood pressure. You could get dizzy or faint.

What are the possible side effects of tadalafil tablets?

The following side effects were reported rarely in patients taking tadalafil:

Decreased eyesight or loss of vision in one or both eyes (NAION). If you notice a sudden decrease or loss of vision in one or both eyes, contact a healthcare provider right away.
Sudden decrease or loss of hearing, sometimes with ringing in the ears and dizziness. If you notice a sudden decrease or loss of hearing, contact a healthcare provider right away.
In men, an erection that lasts more than 4 hours (with or without pain). Talk to your healthcare provider or go to the emergency department right away. An erection that lasts more than 4 hours must be treated as soon as possible or you can have lasting damage to your penis, including the inability to have erections.

See “What is the most important information I should know about tadalafil tablets?”

The most common side effects with tadalafil tablets include:

headache
muscle pain
getting red or hot in the face (flushing)
nausea
pain in the arms, legs, or back
upset stomach

Tell your healthcare provider about any side effect that bothers you or does not go away.

These are not all the possible side effects of tadalafil tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Store tadalafil tablets at room temperature between 59° and 86°F (15° and 30°C).

Keep tadalafil tablets and all medicines out of the reach of children.

General Information about the safe and effective use of tadalafil tablets

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use tadalafil tablets for a condition for which it was not prescribed. Do not give tadalafil tablets to other people, even if they have the same symptoms you have. It may harm them.

This patient information leaflet summarizes the most important information about tadalafil tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about tadalafil tablets that is written for healthcare professionals. For more information you can visit www.lupinpharmaceuticals.com website or call 1-800-399-2561.

What Are The Ingredients In Tadalafil Tablets?

Inactive Ingredients: croscarmellose sodium, hypromellose, iron oxide yellow, iron oxide red, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulphate, talc, titanium dioxide, and triacetin.