Lorlatinib

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# Black Box Warning

# Overview
Lorlatinib is a Antineoplastic Agents that is FDA approved for the treatment of The treatment of patients with lung cancer
- Should not be given to patients who are pregnant or are trying to get pregnant
- This medication is only to be used after confirming the cancer has a ALK gene marker
- The doctor will test for that gene. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include Edema, Peripheral Neuropathy, Cognitive Effects, Dyspnea (shortness of breath), fatigue, weight gain, arthralgia, mood effects, diarrhea.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Lorlatinib is indicated for:
- The treatment of patients with anaplastic lymphoma kinase- aggressive, wide-spread lung cancer
- It is indicated for with:
Crizonitib and another ALK inhibitor, or Alectinib, the first therapy for metastatic disease, or Ceritinib as the first ALK inhibitor for this type of disease
- Crizonitib and another ALK inhibitor, or Alectinib, the first therapy for metastatic disease, or Ceritinib as the first ALK inhibitor for this type of disease

### Limitations of Use
- See adverse reactions
- See specific populations

### Dosing Considerations
- Some dose reductions if the patients have adverse reactions include:
Swallow Lorlatinib orally in a recommended dosage of 75 mg once daily
If there is need for more reduction, take Lorlatinib 50 mg once daily orally
- Swallow Lorlatinib orally in a recommended dosage of 75 mg once daily
- If there is need for more reduction, take Lorlatinib 50 mg once daily orally

### Administration of Lorlatinib
- It is recommended that the patient take 100 mg of Lorlatinib, no matter if they have or have not eaten
- The tablets are meant to be swallowed whole: it is unacceptable to chew, break, split tablets because it will not have the same effect and it could be dangerous
Make sure to not to take them if they are broken, cracked, not in packaging etc
- Make sure to not to take them if they are broken, cracked, not in packaging etc
- It is important that the patient takes the medication the same time each day
The patient may take the forgotten dose if it is more that 4 hours from their next dose
It is really important that they do not take multiple doses at once
- The patient may take the forgotten dose if it is more that 4 hours from their next dose
- It is really important that they do not take multiple doses at once

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Lorlatinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding Lorlatinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Lorlatinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Lorlatinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding Lorlatinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- It is crucial to withhold ingesting Lorlatinib for three plasma half lives for patients taking strong CYP3A inducers
- Mixing them together could lead to serious hepatotoxicity or chemical-driven liver damage

# Warnings

### Serious Central Nervous System Effects
- Seizures, Hallucinations, changes in mood, sleep, mental health are all examples of the side effects
- Reduce the dosage of Lorlatinib depending on the severity of the side effect
- For patients requiring first time reduction, give them 75 mg daily through mouth
- For patients requiring second time reduction, give them 50 mg daily through mouth
- About 54% of patients acquiring this drug may experience Central Nervous system side effects listed above
- Patients will be monitored for the first 1-2 months ingesting Lorbrena, and followed up on after the initial period
- Patients may experience an increase in serum cholesterol and triglycerides
- About 7% of patients in the Study B7461001 required to discontinue the drug for a short period of time, and another 3% of the patients required a dose reduction
- In the same study, 80% of the patients required to instigate lipid-lowering medications because they were not responding to reduction and temporary pause
This may have required a period of adjustment for 21 days to get accustomed to the lipid-lowering medications
- This may have required a period of adjustment for 21 days to get accustomed to the lipid-lowering medications

# Adverse Reactions

## Clinical Trials Experience
Severe Adverse Reactions (32% of 295 Patients)
- Some serious reactions reported in the study were: pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%)
- There were some fatal adverse reactions that occurred in about 2.7% of the patients. Those reactions include pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%)

## Postmarketing Experience
There is limited information regarding Lobrena Postmarketing Experience in the drug label.

# Drug Interactions
- Effects of CYP3A Inducers: Combining CYP3A inducers with Lobrena can decrease plasma concentrations that may dull the effects of the medication.
- It is important to discontinue CYP3A inducers for 3 plasma half-lives before initiating the use of Lorlatinib. Interaction between CYP3A inducers and Lobrena can heighten the severity of the present adverse reactions
- In a study, Lobrena mixed with the CYP3A inducer rifampin shows results of severe hepatoxicity.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
This drug can result in major birth defects or fetal harm during animal studies. It is not clear if it can cause fetal harm in human pregnancies. It is important to note that it should be prohibited to have pregnant women or women who want to carry out a pregnancy take Lobrena. In animal studies, fetal harm includes gastroschisis, rotated limbs, supernumerary digits, vessel abnormalities etc. It should be noted that the effects of this medication for pregnant human women is not listed in the FDA label.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lorlatinib in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Lorlatinib during labor and delivery.

### Nursing Mothers
There is not data from studies that indicate the presence of active metabolites or Lorlatinib in breast-fed milk. Patients should consult their medical professional on how to proceed.

### Pediatric Use
Lorlatinib has not been tested on pediatric patients, so the saftey and well-being of children administered Lorlatinib is unknown.

### Geriatic Use
Based on the limited trial data present, patients over the age of 65 do not require a different dose of Lorlatinib.

### Gender
There is no FDA guidance on the use of Lorlatinib with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Lorlatinib with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Lorlatinib in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Lorlatinib in patients with hepatic impairment.

### Females of Reproductive Potential and Males
Advise males who have female reproductive partners to wear contraception for the duration of ingesting this medication and for 3 months after the final dose. Additionally, there has been data that indicates lower testicular, epididymal, and prostate weights. There is a possibility for male fertility impairment after using Lobrena.

### Immunocompromised Patients
There is no FDA guidance one the use of Lorlatinib in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- It is recommended that the patient take 100 mg of Lorlatinib, no matter if they have or have not eaten
- The tablets are meant to be swallowed whole: it is unacceptable to chew, break, split tablets because it will not have the same effect and it could be dangerous
Make sure to not to take them if they are broken, cracked, not in packaging etc
- Make sure to not to take them if they are broken, cracked, not in packaging etc
- It is important that the patient takes the medication the same time each day
The patient may take the forgotten dose if it is more that 4 hours from their next dose
It is really important that they do not take multiple doses at once
- The patient may take the forgotten dose if it is more that 4 hours from their next dose
- It is really important that they do not take multiple doses at once

### Monitoring
There is limited information regarding Lorlatinib Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Lorlatinib and IV administrations.

# Overdosage
- If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
Lorlatinib is a kinase inhibitor that reverses the activity of Anaplastic lymphoma kinase and other tyrosine kinase inhibitors including ROS1, TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. It also reversed the activity of several mutants of the ALK enzyme. Lolrlatinib is capable of crossing the blood-brain barrier which enebles it to treat spreading metasteses in the brain. The effectiveness of Lorlatinib activity has shown to be dose-dependent and associated with the inhibition of ALK phosphorylation. Patients using Lorlatinib have shown a new control to stop tumor regression despite having used tyrosine kinase inhibitors like crizontinib, alectinib, and/or ceritinib.

## Structure
There is limited information regarding Lorlatinib Structure in the drug label.

## Pharmacodynamics
There is limited information regarding Lorlatinib Pharmacodynamics in the drug label.

## Pharmacokinetics
The Lorlatinib plasma concentration increased proportionally over the dose range of 10 mg or Lobrena to 200 mg. The mean Cmax was 577 ng/mL (42%) and the AUC0-24h was 5650 ngh/mL (39%) in patients with small cell lung cancer.
- This data is for intravenous dosage of Lobrena
Lorlatinib distributed and bound to 66% of plasma proteins, around a concentration of 2.4 micro M
- Lorlatinib distributed and bound to 66% of plasma proteins, around a concentration of 2.4 micro M
- The CV% was 305 L or 28% following a single dose intravenously
- The resulting blood to plasma ratio was 0.99
- Studies showed that the half-life of Lorlatinib plasma was 24 hours after one oral dose
- The oral clearance that resulted was 11 L/h and it eventually increased to 18 L/h which could mean auto-induction, or certain enzymes increased to help faster metabolize the agent
- Pregnancy= This drug can result in major birth defects or fetal harm during animal studies. It is not clear if it can cause fetal harm in human pregnancies. It is important to note that it should be prohibited to have pregnant women or women who want to carry out a pregnancy take Lobrena. In animal studies, fetal harm includes gastroschisis, rotated limbs, supernumerary digits, vessel abnormalities etc. It should be noted that the effects of this medication for pregnant human women is not listed in the FDA label.
- Lactation= Lobrena or any of its metabolites will not contaminate human milk, and it will not effect the production of breastfeeding milk. However, there could be serious adverse reactions for the infants receiving the breastfed milk. Therefore, women should be instructed to abstain from breastfeeding until 7 days after their final dose of Lobrena.
- Geriatric Use= Through the study B7461001, there has been no discrepancies of the effects between patients 65 and older (18 % of the test patients) and patients younger than that
- Pediatric Use: The efficiency and safety of this medication has not been established in pediatric patients.

## Nonclinical Toxicology
There is limited information regarding Lorlatinib Nonclinical Toxicology in the drug label.

# Clinical Studies

### Study in Adult Patients with Anaplastic Lymphoma Kinase 
Study B7461001
- This study was a multinational, multi-cohort trial that welcomed finding the correct dose sizes and the amount of activity of this medication
- It included 295 patients with ALK-positive or ROS1-positive metastatic NSCLC or non-small cell lung cancer
- The patients were given 100 mg of Lorlatinib orally everyday and were monitored for 12.5 months. More than 52% of the patients were exposed to medication for more than 12 months
- The demographics of the patients: 19-85 year old patients- wide range- with the median age being 53 years. 58% of the patients were female. The races were: 49% Caucasian, 37% Asian.
- There were many adverse reactions that were reported in more than 20% of the patients were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea
- There were soem abnormalities that occurred in the lab including  hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase

### Study in Pediatric Patients with Anaplastic Lymphoma Kinase
- There is limited information regarding Lorlatinib Studies in Pediatric Patients

# How Supplied
- It is supplied in a child-resistant vial that contains 25 or 100 mg worth of tablets. There will be 30 tablets in the bottle. Some of the inactive ingredients in the tablet include microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.
The 25 mg bottles will contain tablets that appear as 8mm round, tan-colored, film-coated, and has 25 on one side and LLN on the other side
The 100 mg bottles will contain tablets that appear as 8.5 by 17 mm round, lavender-colored, film-coated, contains Pfizer on on side, and 100 and LLn on the other
- The 25 mg bottles will contain tablets that appear as 8mm round, tan-colored, film-coated, and has 25 on one side and LLN on the other side
- The 100 mg bottles will contain tablets that appear as 8.5 by 17 mm round, lavender-colored, film-coated, contains Pfizer on on side, and 100 and LLn on the other

## Storage
- Lorbrena is stored in a temperature of 20-25 degrees Celsius (68-77 degrees Fahrenheit)
- It is allowed to be exposed to temperatures from 15-30 degrees Celsius for some time

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Patients should be aware that utilizing Lobrena concurrent to CYP3A inducers can lead to serious cases of hepatotoxicity
- Patients should check with a doctor to confirm the compatibility of certain medications with Lobrena

### Serious Central Nervous System Effects
- Seizures, Hallucinations, changes in mood, sleep, mental health are all examples of the side effects
- Reduce the dosage of Lorlatinib depending on the severity of the side effect
- For patients requiring first time reduction, give them 75 mg daily through mouth
- For patients requiring second time reduction, give them 50 mg daily through mouth
- About 54% of patients acquiring this drug may experience Central Nervous system side effects listed above
- Patients will be monitored for the first 1-2 months ingesting Lorbrena, and followed up on after the initial period
- Patients may experience an increase in serum cholesterol and triglycerides
- About 7% of patients in the Study B7461001 required to discontinue the drug for a short period of time, and another 3% of the patients required a dose reduction
- In the same study, 80% of the patients required to instigate lipid-lowering medications because they were not responding to reduction and temporary pause
This may have required a period of adjustment for 21 days to get accustomed to the lipid-lowering medications
- This may have required a period of adjustment for 21 days to get accustomed to the lipid-lowering medications

### Discontinuation
- Patients ingesting Lobrena having serious adverse reactions had to discontinue the drug
- About 1.5% of patients experiencing Central Nervous system adverse effects had to completely discontinue this medication
- Overall, about 8% of patients had to discontinue the drug due to serious side effects like pneumonia, dyspnea, pyrexia, respiratory failure, myocardial infarction, acute pulmonary edema, embolism, peripheral artery occlusion, mental status change to name a few
Some of these reactions led to permanent discontinuation including respiratory failure and dyspnea included at the top
- Some of these reactions led to permanent discontinuation including respiratory failure and dyspnea included at the top

### Infusion reactions
- There is limited information on Lobrena infusion reactions

# Precautions with Alcohol
Alcohol-Lorlatinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
Lorbrena

# Look-Alike Drug Names
There is limited information regarding Lorlatinib Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price