Pitolisant is a medication primarily used to treat narcolepsy, a neurological disorder that affects sleep-wake cycles. It works as a histamine 3 receptor antagonist, which helps to promote wakefulness. Pitolisant is often prescribed to individuals with narcolepsy who experience excessive daytime sleepiness and cataplexy.
Unlike traditional stimulants used to treat narcolepsy, such as amphetamines or methylphenidate, pitolisant has a different mechanism of action and is not classified as a controlled substance. This makes it an attractive option for some patients who may have concerns about the potential for abuse or dependence associated with traditional stimulants.
Pitolisant (Wakix) is a selective antagonist (or inverse agonist) of the H3 (histamine) receptors in the brain that improves wakefulness. It is used in the management of patients with narcolepsy similar to modafinil (but with a unique mechanism of action)
Pitolisant Uses:
- Narcolepsy:
- It is used to treat excessive daytime sleepiness in adult patients with narcolepsy.
Pitolisant (Wakix) Dose in Adults:
The recommended dose is 17.8 to 35.6 mg orally once a day administered early in the morning before meals. The dose is then titrated based on the patients' response and tolerance as follows:
- Week 1: Initiate at a dose of 8.9 mg or two tablets of 4.45 mg daily.
- Week 2: Increase the dose to 17.8 mg as a single tablet of 17.8 mg daily.
- Week 3: The dose may be increased to the maximum daily recommended dose of 35.6 mg daily or two tablets of 17.8 mg daily administered early in the morning.
In case a dose is missed, administering a double dose that day is not recommended. The dose should be taken at the next scheduled time.
Dosage recommendations with concomitant medications:
Coadministration with strong CYP2D6 inhibitors:
- Initiate treatment at a dose of 8.9 mg per day and increase the dose after 7 days to 17.8 mg per day.
- If the patient is on a stable dose of Wakix before initiating CYP2D6, the dose of the treatment should be reduced by half.
Coadministration with strong CYP3A4 inducers:
- CYP3A4 reduces the efficacy of the drug by 50%. For patients who are on 8.9 mg or 17.8 mg stable dose before initiating CYP3A4 treatment initiation, the dose should be double by 50% after 7 days.
- Similarly, if the CYP3A4 treatment is discontinued, the dose should of Wakx should be doubled.
Use in patients who are are known CYP2d6 poor metabolizers:
- Poor CYP2D6 metabolizers should be started on a lower initial dose of 8.9 mg. The dose should be increased after 7 days to a maximum of 17.8 mg per day.
Pitolisant (Wakix) Dose in Children:
Not indicated
Pregnancy Risk Category:
- Pitolisant hasn't undergone testing in human or animal pregnancies, so its effects on pregnant individuals and their babies aren't known.
- However, there haven't been any reports linking the drug to harmful outcomes in fetuses or mothers.
- Despite this, the manufacturer suggests registering pregnant women exposed to the drug in a registry to gather more information.
- Additionally, pitolisant might make hormonal contraceptives less effective, so both males and females of reproductive age using the drug should consider alternative contraception methods while on it and for 21 days after their last dose to prevent unwanted pregnancies.
Use during Lactation:
- The presence of pitolisant in human breast milk isn't confirmed, but it has been found in animal studies.
- This suggests it could possibly be excreted in human breast milk, potentially impacting the health of the infant.
- Therefore, before starting pitolisant treatment in breastfeeding mothers, it's important to carefully consider the benefits and risks of the medication for the mother compared to the potential risks to the infant.
- This ensures informed decision-making regarding the use of pitolisant during lactation.
Dose in Kidney disease:
- For individuals with mild to moderate kidney problems, starting with a lower dose of 8.9 mg of pitolisant is suggested.
- This initial dose can then be gradually increased to a maximum of 17.8 mg per day over the course of a week.
- However, it's important to avoid using pitolisant altogether in cases of severe kidney dysfunction.
- This cautious approach helps to minimize the risk of adverse effects and ensures safer use of the medication in patients with kidney issues.
Dose in Liver disease:
- For individuals with mild to moderate liver dysfunction, it is recommended to start with a lower dose of 8.9 mg of pitolisant.
- This initial dose can then be gradually increased to a maximum of 17.8 mg per day, but this titration should occur over a period of two weeks.
- However, in cases of severe liver dysfunction, the use of pitolisant should be avoided altogether.
- This cautious approach helps to minimize the risk of adverse effects and ensures safer use of the medication in patients with liver issues.
Common Side Effects of Pitolisant (Wakix):
- Central Nervous System:
- Headache
Less Common Side Effects Of Pitolisant (Wakix):
- Cardiovascular:
- Increased Heart Rate
- Central Nervous System:
- Insomnia
- Anxiety
- Hallucination
- Irritability
- Sleep Disturbance
- Cataplexy
- Dermatologic:
- Skin Rash
- Gastrointestinal:
- Nausea
- Abdominal Pain
- Decreased Appetite
- Xerostomia
- Neuromuscular & Skeletal:
- Musculoskeletal Pain
- Respiratory:
- Upper Respiratory Tract Infection
Frequency of side effects Not Defined:
- Cardiovascular:
- Prolonged QT Interval On ECG
- Tachycardia
- Central Nervous System:
- Migraine
- Sleep Paralysis
- Sleep Talking
Contraindications to Pitolisant (Wakix):
Severe hepatic dysfunction (It is extensively processed in the liver, and drug toxicity can be possible).
Warnings and precautions
Longer QT interval
- Pitolisant can cause the QT interval in the heart to become longer, which might lead to heart rhythm problems.
- Patients with existing heart conditions, those taking medications that also lengthen the QT interval, people with low levels of potassium, magnesium, or calcium, and those with kidney or liver issues should be cautious when using this medication.
- Higher doses of pitolisant and patients with kidney or liver problems are at a higher risk of developing QT interval prolongation and heart rhythm issues.
Pitolisant: Drug Interaction
|
CYP2D6 Inhibitors (Moderate) |
May increase the serum concentration of Pitolisant. |
|
CYP3A4 Inducers (Moderate) |
|
|
Haloperidol |
QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTcprolonging effect of Haloperidol. |
|
QT-prolonging Agents (Highest Risk) |
QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. |
|
Risk Factor D (Consider therapy modification) |
|
|
CYP2D6 Inhibitors (Strong) |
May increase the serum concentration of Pitolisant. Management: Reduce the pitolisant dose by 50% if a strong CYP2D6 inhibitor is initiated. For patients receiving strong CYP2D6 inhibitors, initiate pitolisant at 8.9 mg once daily and increase after 7 days to a maximum of 17.8 mg once daily. |
|
CYP3A4 Inducers (Strong) |
|
|
Hormonal Contraceptives |
Pitolisant may decrease the serum concentration of Hormonal Contraceptives. Management: Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with pitolisant and for at least 21 days after discontinuation of pitolisant treatment. |
|
Risk Factor X (Avoid combination) |
|
|
Antihistamines |
May diminish the therapeutic effect of Pitolisant. |
|
Tricyclic Antidepressants |
May diminish the therapeutic effect of Pitolisant. |
Monitoring Parameters:
Liver Function Tests:
- Regular monitoring of liver function tests is essential since pitolisant is primarily metabolized in the liver.
- Any abnormalities in liver function may indicate a need for dose adjustment or discontinuation.
Renal Function Tests:
- Monitoring renal function is crucial as well, particularly because a significant portion of pitolisant metabolites are eliminated through the kidneys.
- Any impairment in kidney function may require dosage adjustments.
ECG (QT Interval):
- Regular ECG monitoring, specifically focusing on the QT interval, helps to detect any potential cardiac issues or abnormalities.
- Pitolisant can affect heart rhythm, so keeping an eye on QT interval prolongation is important to prevent serious heart-related complications.
Heart Rate:
- Monitoring heart rate can help detect any irregularities or changes that may be indicative of cardiovascular side effects associated with pitolisant.
Central Nervous System Side Effects:
- Regular assessment for central nervous system side effects, such as dizziness, headache, or psychiatric symptoms, is necessary.
- This helps ensure early detection and management of any adverse effects on the nervous system.
How to administer Pitolisant (Wakix)?
It is administered in the early morning as a once-daily oral medicine.
Mechanism of action of Pitolisant (Wakix):
- Pitolisant is a medicine that helps people stay awake by working in a special way in the brain.
- It targets certain receptors called H3 receptors, which are involved in controlling wakefulness.
- By blocking these receptors, pitolisant boosts the activity of histamine, a neurotransmitter that helps keep us awake.
- It doesn't affect other histamine receptors, so it's quite specific in its action.
- Additionally, it may influence the release of other important brain chemicals like norepinephrine, acetylcholine, and dopamine, although its impact on dopamine is limited in certain parts of the brain.
- Overall, pitolisant helps promote wakefulness in people who have trouble staying awake due to conditions like narcolepsy. [Ref].
Absorption:
- Pitolisant is quickly absorbed when taken by mouth, with about 90% of the drug being absorbed into the bloodstream after oral administration.
Bioavailability:
- The exact bioavailability of pitolisant has not been determined.
Distribution:
- Pitolisant has the ability to pass through the blood-brain barrier, reaching the brain where it exerts its effects.
Steady-state concentration:
- It typically takes around 5 to 6 days of regular dosing for pitolisant to reach a steady concentration level in the body.
Protein binding:
- A large portion, about 91-96%, of pitolisant binds to proteins in the blood, mainly albumin and alpha-1 glycoprotein.
Metabolism:
- The liver is primarily responsible for metabolizing pitolisant, with enzymes like CYP2D6 and to a lesser extent, CYP3A4, playing a role in this process.
Excretion:
- After undergoing metabolism in the liver, around 63% of pitolisant is eliminated through the kidneys in the form of inactive non-conjugated metabolites.
- Approximately 25% is expelled through the breath, and less than 3% is eliminated via feces.
Half-life elimination:
- Pitolisant has an elimination half-life of roughly 10 to 12 hours, meaning it takes this amount of time for half of the drug to be removed from the body.
International Brand Names of Pitolisant:
- Wakix
Pitolisant Brand Names in Pakistan:
No Brands Available in Pakistan.
Pitolisant is a medication primarily used to treat narcolepsy, a neurological disorder that affects sleep-wake cycles. It works as a histamine 3 receptor antagonist, which helps to promote wakefulness. Pitolisant is often prescribed to individuals with narcolepsy who experience excessive daytime sleepiness and cataplexy.
Unlike traditional stimulants used to treat narcolepsy, such as amphetamines or methylphenidate, pitolisant has a different mechanism of action and is not classified as a controlled substance. This makes it an attractive option for some patients who may have concerns about the potential for abuse or dependence associated with traditional stimulants.
Pitolisant (Wakix) is a selective antagonist (or inverse agonist) of the H3 (histamine) receptors in the brain that improves wakefulness. It is used in the management of patients with narcolepsy similar to modafinil (but with a unique mechanism of action)
Pitolisant Uses:
- Narcolepsy:
- It is used to treat excessive daytime sleepiness in adult patients with narcolepsy.
Pitolisant (Wakix) Dose in Adults:
The recommended dose is 17.8 to 35.6 mg orally once a day administered early in the morning before meals. The dose is then titrated based on the patients' response and tolerance as follows:
- Week 1: Initiate at a dose of 8.9 mg or two tablets of 4.45 mg daily.
- Week 2: Increase the dose to 17.8 mg as a single tablet of 17.8 mg daily.
- Week 3: The dose may be increased to the maximum daily recommended dose of 35.6 mg daily or two tablets of 17.8 mg daily administered early in the morning.
In case a dose is missed, administering a double dose that day is not recommended. The dose should be taken at the next scheduled time.
Dosage recommendations with concomitant medications:
Coadministration with strong CYP2D6 inhibitors:
- Initiate treatment at a dose of 8.9 mg per day and increase the dose after 7 days to 17.8 mg per day.
- If the patient is on a stable dose of Wakix before initiating CYP2D6, the dose of the treatment should be reduced by half.
Coadministration with strong CYP3A4 inducers:
- CYP3A4 reduces the efficacy of the drug by 50%. For patients who are on 8.9 mg or 17.8 mg stable dose before initiating CYP3A4 treatment initiation, the dose should be double by 50% after 7 days.
- Similarly, if the CYP3A4 treatment is discontinued, the dose should of Wakx should be doubled.
Use in patients who are are known CYP2d6 poor metabolizers:
- Poor CYP2D6 metabolizers should be started on a lower initial dose of 8.9 mg. The dose should be increased after 7 days to a maximum of 17.8 mg per day.
Pitolisant (Wakix) Dose in Children:
Not indicated
Pregnancy Risk Category:
- Pitolisant hasn't undergone testing in human or animal pregnancies, so its effects on pregnant individuals and their babies aren't known.
- However, there haven't been any reports linking the drug to harmful outcomes in fetuses or mothers.
- Despite this, the manufacturer suggests registering pregnant women exposed to the drug in a registry to gather more information.
- Additionally, pitolisant might make hormonal contraceptives less effective, so both males and females of reproductive age using the drug should consider alternative contraception methods while on it and for 21 days after their last dose to prevent unwanted pregnancies.
Use during Lactation:
- The presence of pitolisant in human breast milk isn't confirmed, but it has been found in animal studies.
- This suggests it could possibly be excreted in human breast milk, potentially impacting the health of the infant.
- Therefore, before starting pitolisant treatment in breastfeeding mothers, it's important to carefully consider the benefits and risks of the medication for the mother compared to the potential risks to the infant.
- This ensures informed decision-making regarding the use of pitolisant during lactation.
Dose in Kidney disease:
- For individuals with mild to moderate kidney problems, starting with a lower dose of 8.9 mg of pitolisant is suggested.
- This initial dose can then be gradually increased to a maximum of 17.8 mg per day over the course of a week.
- However, it's important to avoid using pitolisant altogether in cases of severe kidney dysfunction.
- This cautious approach helps to minimize the risk of adverse effects and ensures safer use of the medication in patients with kidney issues.
Dose in Liver disease:
- For individuals with mild to moderate liver dysfunction, it is recommended to start with a lower dose of 8.9 mg of pitolisant.
- This initial dose can then be gradually increased to a maximum of 17.8 mg per day, but this titration should occur over a period of two weeks.
- However, in cases of severe liver dysfunction, the use of pitolisant should be avoided altogether.
- This cautious approach helps to minimize the risk of adverse effects and ensures safer use of the medication in patients with liver issues.
Common Side Effects of Pitolisant (Wakix):
- Central Nervous System:
- Headache
Less Common Side Effects Of Pitolisant (Wakix):
- Cardiovascular:
- Increased Heart Rate
- Central Nervous System:
- Insomnia
- Anxiety
- Hallucination
- Irritability
- Sleep Disturbance
- Cataplexy
- Dermatologic:
- Skin Rash
- Gastrointestinal:
- Nausea
- Abdominal Pain
- Decreased Appetite
- Xerostomia
- Neuromuscular & Skeletal:
- Musculoskeletal Pain
- Respiratory:
- Upper Respiratory Tract Infection
Frequency of side effects Not Defined:
- Cardiovascular:
- Prolonged QT Interval On ECG
- Tachycardia
- Central Nervous System:
- Migraine
- Sleep Paralysis
- Sleep Talking
Contraindications to Pitolisant (Wakix):
Severe hepatic dysfunction (It is extensively processed in the liver, and drug toxicity can be possible).
Warnings and precautions
Longer QT interval
- Pitolisant can cause the QT interval in the heart to become longer, which might lead to heart rhythm problems.
- Patients with existing heart conditions, those taking medications that also lengthen the QT interval, people with low levels of potassium, magnesium, or calcium, and those with kidney or liver issues should be cautious when using this medication.
- Higher doses of pitolisant and patients with kidney or liver problems are at a higher risk of developing QT interval prolongation and heart rhythm issues.
Pitolisant: Drug Interaction
|
CYP2D6 Inhibitors (Moderate) |
May increase the serum concentration of Pitolisant. |
|
CYP3A4 Inducers (Moderate) |
|
|
Haloperidol |
QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTcprolonging effect of Haloperidol. |
|
QT-prolonging Agents (Highest Risk) |
QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. |
|
Risk Factor D (Consider therapy modification) |
|
|
CYP2D6 Inhibitors (Strong) |
May increase the serum concentration of Pitolisant. Management: Reduce the pitolisant dose by 50% if a strong CYP2D6 inhibitor is initiated. For patients receiving strong CYP2D6 inhibitors, initiate pitolisant at 8.9 mg once daily and increase after 7 days to a maximum of 17.8 mg once daily. |
|
CYP3A4 Inducers (Strong) |
|
|
Hormonal Contraceptives |
Pitolisant may decrease the serum concentration of Hormonal Contraceptives. Management: Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with pitolisant and for at least 21 days after discontinuation of pitolisant treatment. |
|
Risk Factor X (Avoid combination) |
|
|
Antihistamines |
May diminish the therapeutic effect of Pitolisant. |
|
Tricyclic Antidepressants |
May diminish the therapeutic effect of Pitolisant. |
Monitoring Parameters:
Liver Function Tests:
- Regular monitoring of liver function tests is essential since pitolisant is primarily metabolized in the liver.
- Any abnormalities in liver function may indicate a need for dose adjustment or discontinuation.
Renal Function Tests:
- Monitoring renal function is crucial as well, particularly because a significant portion of pitolisant metabolites are eliminated through the kidneys.
- Any impairment in kidney function may require dosage adjustments.
ECG (QT Interval):
- Regular ECG monitoring, specifically focusing on the QT interval, helps to detect any potential cardiac issues or abnormalities.
- Pitolisant can affect heart rhythm, so keeping an eye on QT interval prolongation is important to prevent serious heart-related complications.
Heart Rate:
- Monitoring heart rate can help detect any irregularities or changes that may be indicative of cardiovascular side effects associated with pitolisant.
Central Nervous System Side Effects:
- Regular assessment for central nervous system side effects, such as dizziness, headache, or psychiatric symptoms, is necessary.
- This helps ensure early detection and management of any adverse effects on the nervous system.
How to administer Pitolisant (Wakix)?
It is administered in the early morning as a once-daily oral medicine.
Mechanism of action of Pitolisant (Wakix):
- Pitolisant is a medicine that helps people stay awake by working in a special way in the brain.
- It targets certain receptors called H3 receptors, which are involved in controlling wakefulness.
- By blocking these receptors, pitolisant boosts the activity of histamine, a neurotransmitter that helps keep us awake.
- It doesn't affect other histamine receptors, so it's quite specific in its action.
- Additionally, it may influence the release of other important brain chemicals like norepinephrine, acetylcholine, and dopamine, although its impact on dopamine is limited in certain parts of the brain.
- Overall, pitolisant helps promote wakefulness in people who have trouble staying awake due to conditions like narcolepsy. [Ref].
Absorption:
- Pitolisant is quickly absorbed when taken by mouth, with about 90% of the drug being absorbed into the bloodstream after oral administration.
Bioavailability:
- The exact bioavailability of pitolisant has not been determined.
Distribution:
- Pitolisant has the ability to pass through the blood-brain barrier, reaching the brain where it exerts its effects.
Steady-state concentration:
- It typically takes around 5 to 6 days of regular dosing for pitolisant to reach a steady concentration level in the body.
Protein binding:
- A large portion, about 91-96%, of pitolisant binds to proteins in the blood, mainly albumin and alpha-1 glycoprotein.
Metabolism:
- The liver is primarily responsible for metabolizing pitolisant, with enzymes like CYP2D6 and to a lesser extent, CYP3A4, playing a role in this process.
Excretion:
- After undergoing metabolism in the liver, around 63% of pitolisant is eliminated through the kidneys in the form of inactive non-conjugated metabolites.
- Approximately 25% is expelled through the breath, and less than 3% is eliminated via feces.
Half-life elimination:
- Pitolisant has an elimination half-life of roughly 10 to 12 hours, meaning it takes this amount of time for half of the drug to be removed from the body.
International Brand Names of Pitolisant:
- Wakix
Pitolisant Brand Names in Pakistan:
No Brands Available in Pakistan
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