Consumer medicine information

Lorviqua

Lorlatinib

BRAND INFORMATION

Brand name

Lorviqua

Active ingredient

Lorlatinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lorviqua.

SUMMARY CMI

Lorviqua®

Consumer Medicine Information (CMI) summary

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

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

1. Why am I using Lorviqua?

Lorviqua contains the active ingredient lorlatinib. Lorviqua is used to treat a rare type of lung cancer that is caused by defects in a gene called anaplastic lymphoma kinase (ALK).

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

2. What should I know before I use Lorviqua?

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

Talk to your doctor if you take any other medicines, or before starting any new medicines as Lorviqua can interact with some medicines. Talk to your doctor if you have any other medical conditions, or are pregnant or plan to become pregnant or are breastfeeding. Do not give this medicine to a child.

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

3. What if I am taking other medicines?

Some medicines may interfere with Lorviqua and affect how it works.

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

4. How do I use Lorviqua?

  • Lorviqua is taken orally (by mouth) once a day. You are encouraged to swallow the tablet whole (do not chew, crush or split), and take it at approximately the same time each day
  • Your doctor will advise how much Lorviqua to take prior to starting treatment

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

5. What should I know while using Lorviqua?

Things you should do
  • Remind any doctor, pharmacist or dentist you visit that you are using Lorviqua
  • Tell your doctor immediately if you become pregnant while using this medicine, or if you develop changes in your heartbeat, lightheadedness, fainting, dizziness or shortness of breath
  • Keep all of your doctors appointments so that your dose and progress can be monitored regularly
Things you should not do
  • Do not stop using this medicine or change the dosage without talking with your doctor
  • Do not give Lorviqua to anyone else, even if they have the same condition as you
Driving or using machines
  • Be careful driving or operating machinery until you know how Lorviqua affects you as you as you may experience neurological symptoms
Looking after your medicine
  • Keep your tablets in the pack/bottle until it is time to take them
  • Store them out of reach of children, in a cool dry place where the temperature stays below 30°C, heat and dampness (e.g., bathroom, window sill or car) may destroy them

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

6. Are there any side effects?

Lorviqua may cause serious side effects, including: liver problems due to interactions with other medicines; neurological problems such as changes in mood, speech or sleep, seizures, hallucinations, or confusion; increases in the cholesterol, triglycerides, or sugar levels in your blood; heart problems, specifically irregular heartbeats; severe swelling (inflammation) of the lungs.

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

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



FULL CMI

Lorviqua®

Active ingredient(s): lorlatinib

Consumer Medicine Information (CMI)

This leaflet provides important information about using Lorviqua. It does not contain all the available information. It does not take the place of you talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Lorviqua against the benefits they expect it will have for you.

You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Lorviqua.

Where to find information in this leaflet:

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

1. Why am I using Lorviqua?

Lorviqua contains the active ingredient lorlatinib.

Lorviqua blocks the action of an enzyme called ‘ALK tyrosine kinase’. Abnormal forms of this enzyme (due to the fault in the ALK gene) help encourage cancer cell growth.

Lorviqua is used to treat a rare type of lung cancer that is caused by defects in a gene called anaplastic lymphoma kinase (ALK).

Lorviqua may slow down or stop the growth of your cancer. It may also help to shrink your cancer.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

Lorviqua is available only with a doctor's prescription.

It is not addictive.

There is not enough information to recommend the use of this medicine for children.

2. What should I know before I use Lorviqua?

Warnings

Do not use Lorviqua if:

  1. You are allergic to lorlatinib, or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include:
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
  1. You are taking any of the following medicines:
  • rifampicin, a medicine used to treat tuberculosis
  • carbamazepine, phenytoin, medicines used to treat epilepsy
  • enzalutamide, a medicine used to treat cancer of the adrenal glands
  • mitotane, a medicine used to treat prostate cancer
  • medicines containing St John's wort (hypericum perforatum, a herbal preparation)

Check with your doctor if:

  • you have been told that you cannot tolerate or digest some sugars. Lorviqua contains lactose, a type of sugar found in milk or dairy products. Always check the ingredients to make sure you can use this medicine
  • you have allergies to any other medicines, food, preservatives or dyes
  • take any medicines for any other condition
  • you have or have had any of the following medical conditions:
    - high levels of blood cholesterol or triglycerides
    - high blood pressure
    - high blood sugar levels (eg., diabetes)
    - heart problems, including reduced heart rate, or if the results of an electrocardiogram (ECG) have shown that you have an abnormality of the electrical activity of your heart known as "prolonged PR interval" or "AV block"
    - high levels of the enzymes known as amylase or lipase in the blood or a condition such as pancreatitis that can raise the levels of these enzymes
    - cough, chest pains, shortness of breath, or worsening of respiratory symptoms or ever had a lung condition called pneumonitis
    - liver problems
    - kidney problems
    - neurological problems

Your doctor should perform blood tests to check the level of cholesterol and triglcerides in your blood before you start treatment with Lorviqua and regularly during treatment

Your blood pressure and blood sugar levels should be controlled before starting treatment with Lorviqua. Your doctor should continue to monitor your levels regularly during treatment.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

  • Do not take Lorviqua if you are pregnant, it may affect your developing baby.
  • Do not breast-feed while taking Lorviqua or for 7 days after the last dose. The active ingredient in Lorviqua may pass into breast milk and there is a possibility that your baby may be affected

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

You should avoid falling pregnant while using this medicine.

Use highly effective contraception (e.g. double-barrier contraception such as condom and diaphragm) during treatment and for at least 21 days after stopping treatment.

Lorviqua may reduce the effectiveness of hormonal contraceptive methods (e.g. birth control pill). If hormonal contraception is unavoidable it must be used with a form of barrier contraception such as a condom.

If your male partner is being treated with Lorviqua, he must use a condom during treatment and for at least 14 weeks after stopping treatment.

Talk to your doctor about the right methods of contraception for you and your partner.

Lorviqua may affect male fertility.

Talk to your doctor about fertility preservation before taking Lorviqua.

If you become pregnant when taking Lorviqua or during the 3 weeks after taking your last dose, tell your doctor straight away.

If you have not told your doctor about any of the above, tell him/her before you start taking Lorviqua.

Do not give this medicine to a child

Safety and effectiveness in children have not been established.

3. What if I am taking other medicines?

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

Some medicines and Lorviqua may interfere with each other. These include:

  • boceprivir, a medicine used to treat hepatitis C
  • medicines used to treat AIDS/HIV such as efavirenz, cobicistat, ritonavir, paritaprevir in combination with ritonavir and ombitasvir and/or dasabuvir, and ritonavir in combination with either danoprevir, elvitegravir, indinavir, lopinavir, saquinavir or tipranavir
  • medicines used to treat fungal infections such as itraconazole, ketoconazole, posaconazole, voriconazole, fluconazole
  • troleandomycin, a medicine used to treat certain types of bacterial infections
  • quinidine, a medicine used to treat irregular heartbeat and other heart problems
  • medicines used to treat severe pain such as alfentanil and fentanyl
  • medicines used to prevent organ transplant rejection such as ciclosporin, sirolimus and tacrolimus

Some medicines may interfere with Lorviqua or affect how it works.

You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

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

4. How do I use Lorviqua?

How much to take

  • The recommended dose is 100 mg taken orally once daily
  • Your doctor may lower your dose, stop your treatment for a short time or stop your treatment completely if you feel unwell

Swallow the tablets whole and do not crush, chew or split the tablets

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet. If you do not understand the instructions on the box/bottle, ask your doctor or pharmacist for help.

When to take Lorviqua

  • Take your medicine at about the same time each day to have the best effect and to help you remember when to take it.
  • It does not matter if you take this medicine before or after food. However, you should avoid eating grapefruit or drinking grapefruit juice while taking Lorviqua.

How long to take Lorviqua

Continue taking your medicine for as long as your doctor tells you.

If you forget to take Lorviqua

Lorviqua should be taken regularly at the same time each day.

If you miss your dose at the usual time, if it is less than 4 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much Lorviqua

If you think that you have taken too much Lorviqua, you may need urgent medical attention.

You should immediately:

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

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

5. What should I know while using Lorviqua?

Things you should do

  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Lorviqua
  • Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine
  • If you become pregnant while taking this medicine, tell your doctor immediately

Call your doctor straight away if you develop:

  • changes in your heartbeat (fast or slow), light-headedness, fainting, dizziness or shortness of breath.
Your doctor may do some tests (electrocardiograms) to check that there are no problems with your heart during treatment with Lorviqua. If the results are abnormal he/she may decide to reduce your dose or stop your treatment.
  • difficulty speaking, including slurred or slow speech
  • change in your mood (including depression, euphoria and mood swings), feelings of irritability, aggression, agitation, anxiety or a change in your personality, memory loss or impairment, episodes of confusion

Tell your doctor if you notice any of the following:

  • you feel more tired than usual
  • your skin and whites of your eyes turn yellow
  • your urine turns dark brown (tea colour)
  • you have nausea, vomiting or decreased appetite
  • you have pain in the upper area of and/or on the right side of your stomach
  • you have itching
  • you bruise more easily than usual
  • you develop a fever
  • you develop a cough, chest pains, shortness of breath, or worsening of respiratory symptoms.

Your doctor may do some tests (blood tests, scans) to check your liver function and pancreas. If the results are abnormal he/she may decide to reduce your dose or stop your treatment.

Your doctor should continue to monitor your blood pressure and blood sugar levels regularly during treatment.

Keep all of your doctor's appointments so that your progress can be checked.

Remind any doctor or dentist you visit that you are using Lorviqua.

Things you should not do

  • Do not stop using this medicine suddenly or lower the dosage without checking with your doctor
  • Do not take Lorviqua to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.

If you are not able to take the medicine as your doctor has prescribed, contact your doctor right away.

Driving or using machines

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

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Follow the instructions in the carton on how to take care of your medicine properly
  • Keep your tablets in the pack/bottle until it is time to take them

Store it in a cool dry place away from moisture, heat or sunlight; below 30°C. For example, do not store it:

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

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

Keep it where young children cannot reach it.

Keep Lorviqua in a locked cupboard at least one-and-a-half metres above the ground.

Getting rid of any unwanted medicine

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

6. Are there any side effects?

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

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

Serious side effects

Serious side effectsWhat to do
Allergic type reactions
  • swelling of the skin or limbs
Nervous system
  • feeling of pain, numbness, burning, or pins and needles in your arms or legs
  • problems with your eyes such as difficulty seeing out of one or both eyes, double vision or perceived flashes of light
  • seizures
  • difficulty walking or performing usual activities such as writing
  • changes in speech, including difficulty speaking, such as slurred or slow speech
  • effects on memory, including confusion, memory loss and disturbance of attention
Psychiatric disorders
  • changes in mood, including mood swings
  • seeing or hearing things that are not real (hallucinations)
Vascular disorders
  • high blood pressure*
Muscle related issues
  • pain in your joints
Stomach related issues
  • Diarrhea
  • Constipation
Metabolism
  • weight gain
  • changes in cholesterol and/or triglyceride levels*
  • high blood sugar levels*
General disorders
  • tiredness

*These side effects may show up when you have a blood test.

Call your doctor straight away if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

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

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

7. Product details

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

What Lorviqua contains

Active ingredient
(main ingredient)		lorlatinib
Other ingredients
(inactive ingredients)

microcrystalline cellulose

calcium hydrogen phosphate

sodium starch glycollate

magnesium stearate

hypromellose (E464)

lactose monohydrate

macrogol 3350

triacetin

titanium dioxide (E171)

iron oxide black (E172)

iron oxide red (E172)

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

What Lorviqua looks like

Lorviqua 25 mg tablets are round tan coloured film-coated tablets debossed with "Pfizer" on one side and "25" and "LLN" on the other side.

Lorviqua 25 mg tablets are available as blister packs containing 90 or 120 tablets and in bottles containing 30 tablets.

(AUST R 310778 (blister pack)

(AUST R 310781 (bottle)

Lorviqua 100 mg tablets are oval lavender coloured film-coated tablets debossed with "Pfizer" on one side and "LLN 100" on the other side.

Lorviqua 100 mg tablets are available as blister packs and in bottles containing 30 tablets.

(AUST R 310780 (blister pack)

(AUST R 310779 (bottle)

Who distributes Lorviqua

Lorviqua is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

This leaflet was prepared in December 2021.

Published by MIMS March 2022

BRAND INFORMATION

Brand name

Lorviqua

Active ingredient

Lorlatinib

Schedule

S4

 

1 Name of Medicine

Lorlatinib.

2 Qualitative and Quantitative Composition

Each 25 mg film coated tablet contains 25 mg of lorlatinib.

Excipient with known effect.

1.58 mg of lactose per film coated tablet.
Each 100 mg film coated tablet contains 100 mg of lorlatinib.

Excipient with known effect.

4.20 mg of lactose per film coated tablet.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablet, film coated.
25 mg: 8 mm round tan film coated tablet, debossed with "Pfizer" on one side and "25" and "LLN" on the other side.
100 mg: oval (8.5 x 17 mm) lavender film coated tablet, debossed with "Pfizer" on one side and "LLN 100" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Lorviqua is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK) positive locally advanced or metastatic non small cell lung cancer (NSCLC), as determined by a validated test.

4.2 Dose and Method of Administration

ALK-positive status should be established using a validated ALK assay prior to initiation of lorlatinib therapy.

Recommended dosing.

The recommended dose of Lorviqua is 100 mg taken orally once daily. Continue treatment for as long as the patient is deriving clinical benefit from therapy.
Lorviqua may be taken with or without food (see Section 5.2).
Patients should be encouraged to take their dose of Lorviqua at approximately the same time each day. Tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked or otherwise not intact.
If a dose of Lorviqua is missed, then it should be taken as soon as the patient remembers unless it is less than 4 hours before the next dose, in which case the patient should not take the missed dose. Patients should not take 2 doses at the same time to make up for a missed dose.

Dose modifications.

Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. Dose reduction levels are summarised below.
First dose reduction: Lorviqua 75 mg taken orally once daily.
Second dose reduction: Lorviqua 50 mg taken orally once daily.
Lorviqua should be permanently discontinued if the patient is unable to tolerate Lorviqua 50 mg taken orally once daily.
Dose modification recommendations for toxicities and for patients who develop first degree, second degree, or complete atrioventricular (AV) block are provided in Table 1.

Strong cytochrome P-450 (CYP) 3A inhibitors.

Concurrent use of Lorviqua with strong CYP3A inhibitors may increase lorlatinib plasma concentrations. An alternative concomitant medicinal product with less potential to inhibit CYP3A should be considered (see Section 4.5; Section 5.2). If a strong CYP3A inhibitor must be co administered, the starting Lorviqua dose of 100 mg once daily should be reduced to once daily 75 mg dose.
In patients who have had a dose reduction to 75 mg orally once daily due to adverse reactions and who initiate a strong CYP3A inhibitor, reduce the Lorviqua dose to 50 mg orally once daily.
If concurrent use of a strong CYP3A inhibitor is discontinued, Lorviqua should be resumed at the dose used prior to the initiation of the strong CYP3A inhibitor and after a washout period of 3 to 5 half lives of the strong CYP3A inhibitor.

Fluconazole.

Avoid concomitant use of Lorviqua with fluconazole (see Section 4.5). If concomitant use is unavoidable, reduce the starting dose of Lorviqua from 100 mg orally once daily to 75 mg orally once daily.

Hepatic impairment.

No dose adjustments are recommended for patients with mild hepatic impairment. Limited information is available for lorlatinib in patients with moderate or severe hepatic impairment. Therefore, Lorviqua is not recommended in patients with moderate to severe hepatic impairment (see Section 5.2).

Renal impairment.

No dose adjustment is needed for patients with mild or moderate renal impairment [absolute estimated glomerular filtration rate (eGFR): ≥ 30 mL/min]. A reduced dose of Lorviqua is recommended in patients with severe renal impairment (absolute eGFR < 30 mL/min), e.g. a starting dose of 75 mg taken orally once daily (see Section 5.2).

Elderly (≥ 65 years).

The limited data on the safety and efficacy of Lorviqua in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients (see Section 5.2).

Paediatric patients.

The safety and efficacy of Lorviqua in paediatric patients has not been established.

4.3 Contraindications

Hypersensitivity to lorlatinib or to any of the excipients listed in Section 6.1.
Concomitant use of strong CYP3A inducers with Lorviqua is contraindicated due to the potential for serious hepatotoxicity (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] elevations) (see Section 4.4; Section 4.5).

4.4 Special Warnings and Precautions for Use

ALK-positive status should be established using a validated ALK assay.

Hyperlipidaemia.

The use of Lorviqua has been associated with increases in serum cholesterol and triglycerides (see Section 4.8). Serum cholesterol and triglycerides should be monitored before initiation with Lorviqua, for 2, 4, and 8 weeks after initiating Lorviqua and periodically thereafter. Initiation, or increase in the dose, of lipid lowering agents is required (see Section 4.2).

Central nervous system effects.

Central nervous system (CNS) effects have been observed in patients receiving Lorviqua including psychotic effects, seizures, changes in cognitive function, mood, speech, and mental status changes (see Section 4.8). Dose modification or discontinuation may be required for those patients who develop CNS effects (see Section 4.2).

Atrioventricular block.

PR interval prolongation and AV block events have been reported in patients receiving Lorviqua. Monitor electrocardiogram (ECG) prior to initiating Lorviqua and monthly thereafter, particularly in patients with predisposing conditions to the occurrence of clinically significant cardiac events. Dose modification may be required for those patients who develop AV block (see Section 4.2).

Lipase and amylase increase.

Elevations of lipase and/or amylase have occurred in patients receiving lorlatinib (see Section 4.8). Median time of occurrence of increase in serum lipase and amylase is 70 days (range: 7 to 696 days) and 41 days (range: 7 to 489 days), respectively. Risk of pancreatitis should be considered in patients receiving lorlatinib due to concomitant hypertriglyceridaemia and/or a potential intrinsic mechanism. Patients should be monitored for lipase and amylase elevations prior to the start of lorlatinib treatment and regularly thereafter as clinically indicated (see Section 4.2).

Interstitial lung disease (ILD)/pneumonitis.

Severe or life-threatening pulmonary adverse drug reactions consistent with pneumonitis have occurred with lorlatinib (see Section 4.8). Any patient who presents with worsening of respiratory symptoms indicative of pneumonitis (e.g. dyspnoea, cough, and fever) should be promptly evaluated for pneumonitis. Lorviqua should be withheld and/or permanently discontinued based on severity (see Section 4.2).

Hypertension.

Hypertension has been reported in patients receiving lorlatinib (see Section 4.8). Blood pressure should be controlled prior to initiation of lorlatinib. Blood pressure should be monitored after 2 weeks and at least monthly thereafter during treatment with lorlatinib. Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity (see Section 4.2).

Hyperglycaemia.

Hyperglycaemia has occurred in patients receiving lorlatinib (see Section 4.8). Fasting serum glucose should be assessed prior to initiation of lorlatinib and monitored periodically thereafter. Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity (see Section 4.2).

Risk of serious hepatotoxicity with concomitant use of strong CYP3A inducers.

In a study conducted in healthy volunteers, the concomitant use of Lorviqua and rifampicin, a strong CYP3A inducer, was associated with increases of ALT and AST with no increase of total bilirubin and alkaline phosphatase (see Section 4.5). Concomitant use of a strong CYP3A inducer is contraindicated (see Section 4.3; Section 4.5). Any strong CYP3A inducers have to be discontinued for at least 3 plasma half-lives of the strong CYP3A inducer before Lorviqua treatment is started. No clinically meaningful changes in liver function tests were seen in healthy subjects after receiving a combination of lorlatinib with the moderate CYP3A inducer modafinil (see Section 4.5).
Avoid concomitant use of Lorviqua with moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers cannot be avoided, monitor AST, ALT, and bilirubin 48 hours after initiating Lorviqua and at least 3 times during the first week after initiating Lorviqua.
Depending upon the relative importance of each drug, discontinue Lorviqua or the CYP3A inducer for persistent Grade 2 or higher hepatotoxicity.

Fertility and pregnancy.

Based on animal data and mechanism of action, there is a risk of fetal harm if exposed to Lorviqua (see Section 5.1; Section 5.3). Women of childbearing potential should be advised to avoid becoming pregnant while receiving Lorviqua. A highly effective non-hormonal method of contraception is required for female patients during treatment with Lorviqua because lorlatinib can render hormonal contraceptives ineffective (see Section 4.5; Section 4.6). If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method. Effective contraception must be continued for at least 21 days after completing therapy.
During treatment with Lorviqua and for at least 14 weeks after the final dose, male patients with female partners of reproductive potential must use effective contraception, including a condom, and male patients with pregnant partners must use condoms (see Section 4.6). Male fertility may be compromised during treatment with Lorviqua (see Section 5.3). Men should seek advice on effective fertility preservation before treatment.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro data indicate that lorlatinib is primarily metabolised by CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.

Effect of medicinal products on lorlatinib.

CYP3A inhibitors.

Itraconazole, a strong inhibitor of CYP3A, administered at a dose of 200 mg once daily for 5 days, increased the mean area under the curve (AUC) 42% and Cmax 24% of a single 100 mg oral dose of lorlatinib in healthy volunteers. Concomitant administration of Lorviqua with strong CYP3A inhibitors (e.g., boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, telaprevir, troleandomycin, voriconazole, ritonavir, paritaprevir in combination with ritonavir and ombitasvir and/or dasabuvir, and ritonavir in combination with either danoprevir, elvitegravir, indinavir, lopinavir, saquinavir, or tipranavir) may increase lorlatinib plasma concentrations. Grapefruit products may also increase lorlatinib plasma concentrations. Thus, use of a concomitant strong CYP3A inhibitor should be avoided, or an alternative concomitant medicinal product with less potential to inhibit CYP3A should be considered. If use of a concomitant strong CYP3A inhibitor cannot be avoided, a dose reduction of Lorviqua is recommended (see Section 4.2). Note that a dose reduction of lorlatinib may not sufficiently mitigate the risk associated with lorlatinib exposure increase with concomitant strong CYP3A inhibitor use.

Fluconazole.

Concomitant use of Lorviqua with fluconazole may increase lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of Lorviqua. Avoid concomitant use of Lorviqua with fluconazole. If concomitant use cannot be avoided, reduce the Lorviqua dosage (see Section 4.2).

CYP3A inducers.

Rifampicin, a strong inducer of CYP3A, administered at a dose of 600 mg once daily for 9 days, reduced the mean lorlatinib AUC by 85% and Cmax by 76% of a single 100 mg dose of lorlatinib in healthy volunteers; increases in liver function tests (AST and ALT) were also observed. Concomitant administration of Lorviqua with strong CYP3A inducers (e.g., rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John's wort) may decrease lorlatinib plasma concentrations. The use of a strong CYP3A inducer with Lorviqua is contraindicated (see Section 4.3; Section 4.4). Any strong CYP3A inducers have to be discontinued for at least 3 plasma half-lives of the strong CYP3A inducer before treatment with Lorviqua is started. No clinically meaningful changes in liver function test results were seen after administration of the combination of a single 100 mg oral dose of lorlatinib with the moderate CYP3A inducer, modafinil (400 mg once daily for 19 days) in healthy volunteers. Concomitant use of modafinil did not have a clinically meaningful effect on lorlatinib pharmacokinetics.

Proton pump inhibitors, H2-receptor antagonists, or locally acting antacids.

The proton-pump inhibitor rabeprazole had a minimal effect on lorlatinib plasma exposure (90% confidence interval [CI] for the AUCinf ratio, expressed as a percentage: 97.6%, 104.3%). No dose adjustment is required when Lorviqua is taken with proton-pump inhibitors, H2-receptor antagonists, or locally acting antacids.

Effect of lorlatinib on other medicinal products.

CYP3A substrates.

Lorlatinib has a net induction effect on CYP3A both in vitro and in vivo. Lorlatinib 150 mg orally once daily for 15 days decreased AUCinf by 64% and Cmax by 50% of a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate). Thus, concurrent administration of Lorviqua with CYP3A substrates with narrow therapeutic indices, including but not limited to hormonal contraceptives, alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, should be avoided since the concentration of these drugs may be reduced by lorlatinib.

CYP2B6 substrates.

Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral 100 mg dose of bupropion (a combined CYP2B6 and CYP3A4 substrate) by 25% and 27%, respectively. Thus, lorlatinib is a weak inducer of CYP2B6, and no dose adjustment is necessary when lorlatinib is used in combination with medicinal products that are mainly metabolised by CYP2B6.

CYP2C9 substrates.

Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral 500 mg dose of tolbutamide (a sensitive CYP2C9 substrate) by 43% and 15%, respectively. Thus, lorlatinib is a weak inducer of CYP2C9, and no dose adjustment is required for medicinal products that are mainly metabolised by CYP2C9.
However, patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by CYP2C9 (e.g. coumarin anticoagulants).

UGT substrates.

Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral 500 mg dose of acetaminophen (a UGT, SULT and CYP1A2, 2A6, 2D6, and 3A4 substrate) by 45% and 28%, respectively. Thus, lorlatinib is a weak inducer of UGT, and no dose adjustment is required for medicinal products that are mainly metabolised by UGT.
However, patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by UGT.

P-gp substrates.

Lorlatinib 100 mg once daily for 15 days decreased AUCinf and Cmax of a single oral dose of 60 mg fexofenadine [a sensitive P-glycoprotein (P-gp) substrate] by 67% and 63%, respectively. Thus, lorlatinib is a moderate inducer of P-gp. Medicinal products that are P-gp substrates with narrow therapeutic indices (e.g. digoxin, dabigatran etexilate) should be used with caution in combination with lorlatinib due to the likelihood of reduced plasma concentrations of these substrates.

In vitro inhibition and induction studies of other CYP enzymes.

In vitro studies indicated that clinical drug-drug interactions as a result of lorlatinib-mediated inhibition of the metabolism of substrates for CYP1A2, CYP2C8, CYP2C19 and CYP2D6 are unlikely to occur.
In vitro, lorlatinib has a low potential to cause drug-drug interactions by induction of CYP1A2. In vitro, the major circulating metabolite (M8) of lorlatinib showed a low potential to cause drug drug interaction by inhibiting CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A, or by inducing CYP1A2, CYP2B6, and CYP3A.

In vitro studies with drug transporters other than P-gp.

In vitro studies indicated that lorlatinib may have the potential to inhibit BCRP (gastrointestinal tract), OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 at clinically relevant concentrations. Lorlatinib should be used with caution in combination with substrates of BCRP, OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 as clinically relevant changes in the plasma exposure of these substrates cannot be ruled out.

4.6 Fertility, Pregnancy and Lactation

Women of childbearing potential/contraception in females and males.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving Lorviqua. A highly effective non-hormonal method of contraception is required for female patients during treatment with Lorviqua, because lorlatinib can render hormonal contraceptives ineffective (see Section 4.4; Section 4.5). If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method. Effective contraception must be continued for at least 21 days after completing therapy.
During treatment with Lorviqua and for at least 14 weeks after the final dose, advise male patients with female partners of reproductive potential to use effective contraception, including a condom, and advise male patients with pregnant partners to use condoms.

Effects on fertility.

Dedicated fertility studies were not conducted with lorlatinib. Effects on male reproductive organs were observed in repeat dose toxicity studies and included lower testicular, epididymal and prostate weights; testicular tubular degeneration/atrophy; prostatic atrophy; and/or epididymal inflammation at 20 mg/kg/day and 7 mg/kg/day in rats and dogs, respectively (approximately 4 and 1.6 times the human clinical exposure at 100 mg based on AUC). The effects on male reproductive organs were fully or partially reversible.
Based on nonclinical safety findings, male fertility may be compromised during treatment with Lorviqua. It is not known whether Lorviqua affects female fertility. Men should seek advice on effective fertility preservation before treatment.
(Category D)
Based on findings from animal studies and its mechanism of action, Lorviqua can cause embryo-fetal harm when administered to a pregnant woman. There are no data in pregnant women using Lorviqua.
Administration of lorlatinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in embryolethality, abortions and malformations. Fetal morphologic abnormalities included rotated limbs, supernumerary digits, gastroschisis, malformed kidneys, domed head, high arched palate, and dilation of ventricles of the brain. The lowest doses with embryo-fetal effects in animals correlated with 0.6 to 1.1 times the human clinical exposure at 100 mg, based on AUC.
Lorviqua is not recommended during pregnancy or for women of childbearing potential not using contraception.
 It is not known whether lorlatinib and its metabolites are excreted in human milk. A risk to the newborn child cannot be excluded.
Lorviqua should not be used during breastfeeding. Breastfeeding should be discontinued during treatment with Lorviqua and for 7 days after the last dose.

4.7 Effects on Ability to Drive and Use Machines

Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience CNS effects (see Section 4.8).

4.8 Adverse Effects (Undesirable Effects)

Summary of safety profile.

The data described below reflect exposure to Lorviqua in 476 adult patients with ALK positive or c-ros oncogene 1 (ROS1) positive metastatic NSCLC who received Lorviqua 100 mg orally once daily in single-arm Study B7461001 or randomised, open-label, active-controlled Phase 3 Study B7461006.
The median duration of treatment was 16.3 months (range: 0 day to 55 months), the median age was 55 years (range: 19 to 90 years), and 25% of patients were older than 65 years. A total of 57% of patients were female, 50% of patients were White, 39% of patients were Asian, and 1% were Black.
The most frequently reported adverse drug reactions were hypercholesterolaemia (81.1%), hypertriglyceridaemia (67.2%), oedema (55.7%), peripheral neuropathy (43.7%), weight increased (30.9%), cognitive effects (27.7%), fatigue (27.3%), arthralgia (23.5%), diarrhoea (22.9%), and mood effects (21%).
Serious adverse drug reactions were reported in 7.4% patients receiving lorlatinib. The most frequent serious adverse drug reactions were cognitive effects and pneumonitis.
Dose reductions due to adverse drug reactions occurred in 20.0% of patients receiving lorlatinib. The most common adverse drug reactions that led to dose reductions were oedema and peripheral neuropathy. Permanent treatment discontinuation associated with adverse drug reactions occurred in 3.2% of patients receiving lorlatinib. The most frequent adverse drug reactions that led to a permanent discontinuation were cognitive effects, peripheral neuropathy, and pneumonitis.
Table 2 presents adverse drug reactions for Lorviqua by system organ class (SOC) and CIOMS frequency categories, defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Within each SOC and frequency category, undesirable effects are presented in order of decreasing medical seriousness or clinical importance.

Description of selected adverse drug reactions.

Hypercholesterolaemia/hypertriglyceridaemia.

In clinical trials of patients with ALK-positive or c-ros oncogene 1 (ROS1)-positive metastatic NSCLC, adverse drug reactions of increase in serum cholesterol or triglycerides were reported in 81.1% and 67.2% of patients, respectively. Mild or moderate adverse drug reactions of hypercholesterolaemia or hypertriglyceridaemia occurred in 62.8% and 47.9% of patients, respectively. No patient was discontinued from treatment with lorlatinib due to hypercholesterolaemia or hypertriglyceridaemia (see Section 4.2; Section 4.4). The median time to onset for both hypercholesterolaemia and hypertriglyceridaemia was 15 days. The median duration of hypercholesterolaemia and hypertriglyceridaemia was 450 and 427 days, respectively.

Central nervous system effects.

In clinical trials of patients with ALK-positive or c-ros oncogene 1 (ROS1)-positive metastatic NSCLC, CNS adverse drug reactions were primarily cognitive effects (27.7%), mood effects (21%), speech effects (8.2%), and psychotic effects (6.9%), and were generally mild, transient, and reversible upon dose delay and/or dose reduction (see Section 4.2; Section 4.4). The most frequent cognitive effect of any grade was memory impairment (11.3%), and the most frequent Grade 3 or 4 reactions were cognitive disorder and confusional state (0.8% and 1.7%, respectively). The most frequent mood effect of any grade was anxiety (6.5%), and the most common Grade 3 and 4 reactions were irritability and depression (0.8% and 0.4%, respectively). The most frequent speech effect of any grade was dysarthria (4%), and the most frequent Grade 3 or 4 reactions were dysarthria, slow speech, and speech disorder (0.2% each). The most frequent psychotic effect of any grade was hallucination (2.9%) and the most frequent Grade 3 or 4 reactions were hallucination auditory and hallucination visual (0.2% each).
Median time to onset for cognitive, mood, speech, and psychotic effects was 109, 43, 49 and 23 days, respectively. Median duration of cognitive, mood, speech, and psychotic effects was 223, 143, 147 and 78 days, respectively.

Reporting of suspected adverse reactions.

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

4.9 Overdose

Treatment of overdose with the medicinal product consists of general supportive measures. Given the dose dependent effect on PR interval, ECG monitoring is recommended. There is no antidote for lorlatinib.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Lorlatinib is an adenosine triphosphate (ATP) competitive, brain-penetrant, small molecule inhibitor of ALK and ROS1 tyrosine kinases that addresses mechanisms of resistance following previous treatment with ALK inhibitor therapy.
In nonclinical studies, lorlatinib inhibited catalytic activities of non mutated ALK and a broad range of clinically relevant ALK mutant kinases in recombinant enzyme and cell-based assays. The ALK mutations analyzed included those conferring resistance to other ALK inhibitors, including alectinib, brigatinib, ceritinib, and crizotinib.
Lorlatinib demonstrated anti-tumour activity at nanomolar free plasma concentrations in mice bearing tumour xenografts that express echinoderm microtubule associated protein like 4 (EML4) fusions with ALK variant 1 (v1), including ALK mutations L1196M, G1269A, G1202R, and I1171T. Two of these ALK mutants, G1202R and I1171T, are known to confer resistance to first and second generation ALK inhibitors. Lorlatinib is also capable of penetrating the blood brain barrier and achieved efficacious brain exposure in mice and rat. In mice bearing orthotopic EML4-ALK or EML4-ALKL1196M brain tumour implants, lorlatinib caused tumour shrinkage and prolonged survival. The overall anti-tumour efficacy of lorlatinib was dose-dependent and strongly correlated with inhibition of ALK phosphorylation.

Clinical studies.

Previously untreated ALK-positive advanced NSCLC (CROWN study).

The efficacy of lorlatinib for the treatment of patients with ALK-positive NSCLC who had not received prior systemic therapy for metastatic disease was established in an open-label, randomised, active-controlled, multicentre Study B7461006 (CROWN Study). Patients were required to have an ECOG performance status of 0-2 and ALK-positive NSCLC as identified by the VENTANA ALK (D5F3) CDx assay. Neurologically stable patients with treated or untreated asymptomatic central nervous system (CNS) metastases, including leptomeningeal metastases, were eligible. Patients were required to have finished radiation therapy, including stereotactic or partial brain irradiation within 2 weeks prior to randomisation; whole brain irradiation within 4 weeks prior to randomisation.
Patients were randomised 1:1 to receive lorlatinib 100 mg orally once daily or crizotinib 250 mg orally twice daily. Randomisation was stratified by ethnic origin (Asian vs. non-Asian) and the presence or absence of CNS metastases at baseline. Treatment on both arms was continued until disease progression or unacceptable toxicity. The major efficacy outcome measure was progression-free survival (PFS) as determined by Blinded Independent Central Review (BICR) according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (v1.1). Additional efficacy outcome measures were overall survival (OS), objective response rate (ORR), duration of response (DOR), time to intracranial progression (IC-TTP) all by BICR. In patients with measurable CNS metastases at baseline, additional outcome measures were intracranial objective response rate (IC-ORR) and intracranial duration of response (IC-DOR) all by BICR. See Table 3.
A total of 296 patients were randomised to lorlatinib (n=149) or crizotinib (n=147). The demographic characteristics of the overall study population were: median age 59 years (range: 26 to 90 years), age ≥ 65 years (35%), 59% female, 49% White, 44% Asian, and 0.3% Black. The majority of patients had adenocarcinoma (95%) and never smoked (59%). CNS metastases as determined by BICR neuroradiologists were present in 26% (n=78) of patients: of these, 30 patients had measurable CNS lesions.
Results from the CROWN Study demonstrated a significant improvement in PFS for the lorlatinib arm over the crizotinib arm. The benefit from lorlatinib treatment was comparable across subgroups of baseline patient and disease characteristics. There was a lower incidence of progression in the CNS as the first site of disease progression, alone or with concurrent systemic progression, 3% in the lorlatinib arm compared to 24% in the crizotinib arm [hazard ratio (95% CI) for time to cause-specific CNS progression: 0.06 (0.02, 0.18)]. Efficacy results from the CROWN Study as assessed by BICR are summarised in Table 3 and Figure 1. At the data cut-off point overall survival data was not mature.
The results of prespecified exploratory analyses of intracranial response rate in 30 patients with measurable CNS lesions at baseline as assessed by BICR are summarised in Table 4. Of these, no patients received prior brain radiation.

ALK-positive advanced NSCLC previously treated with an ALK kinase inhibitor.

The use of Lorviqua in the treatment of ALK positive advanced NSCLC previously treated with 1 or more ALK TKIs was investigated in Study B7461001, a single arm, multicenter Phase 1/2 study. A total of 197 patients with ALK positive advanced NSCLC previously treated with 1 or more ALK TKIs were enrolled in the Phase 2 portion of the study. Eligible patients had evidence of histologically or cytologically confirmed diagnosis of metastatic NSCLC that carried an ALK rearrangement, as determined by fluorescence in situ hybridisation (FISH) assay or by Immunohistochemistry (IHC). Patients received Lorviqua orally at the recommended dose of 100 mg once daily, continuously.
The primary efficacy endpoint in the Phase 2 portion of the study was ORR, including intracranial ORR, as per Independent Central Review (ICR) according to modified Response Evaluation Criteria in Solid Tumours (modified RECIST version 1.1). Secondary endpoints included DOR, intracranial DOR, time to tumour response (TTR), and progression free survival (PFS).
Patient demographics of the 197 ALK positive advanced NSCLC patients previously treated with 1 or more ALK TKIs, were 59% female, 49% Caucasian, 36% Asian and the mean age was 53 years (range: 29 to 85 years) with 19% ≥ 65 years of age. The Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 or 1 in 97% of patients and 2 in 4% of patients.70 Brain metastases were present at baseline in 67% of patients. All 197 patients had received prior systemic therapy, 20% received 1, 28% received 2, 19% received 3 and 34% received 4 or more prior systemic therapies. Of the 197 patients, 44% received 1 prior ALK TKI, 33% received 2 prior ALK TKIs, and 23% received 3 or more prior ALK TKIs.
The main efficacy results for Study B7461001 are included in Tables 5 and 6.
Among the 93 patients with a confirmed objective response by ICR, the median TTR was 1.4 months (range: 1.1 to 11.0 months). Among the 70 patients with a confirmed objective tumour response by ICR, the median intracranial TTR was 1.4 months (range: 1.1 to 6.2 months).

5.2 Pharmacokinetic Properties

Absorption.

Peak lorlatinib concentrations in plasma are rapidly reached with the median Tmax of 1.2 hours following a single 100 mg dose and 2.0 hours following 100 mg once daily multiple dosing.
After oral administration of Lorviqua, the mean absolute bioavailability is 80.8% (90% CI: 75.7%, 86.2%) compared to intravenous administration.
Administration of lorlatinib with a high fat, high calorie meal resulted in 5% higher exposure compared to overnight fasting (AUCinf ratio of 104.7%; 90% CI for the ratio: 101.3%, 108.3%). Lorviqua may be administered with or without food. The proton pump inhibitor rabeprazole had a minimal effect on lorlatinib plasma exposure (AUCinf ratio of 100.9%; 90% CI for the ratio: 97.6%, 104.3%). No dose adjustment is recommended when Lorviqua is taken with proton pump inhibitors, H2-receptor antagonists or locally acting antacids.
After multiple once daily dose administration, lorlatinib Cmax increased dose-proportionally and AUCtau increased slightly less than proportionally over the dose range of 10 to 200 mg once daily. At the 100 mg once daily lorlatinib dose, the geometric mean peak plasma concentration was 577 nanogram/mL and the AUC24 5650 nanogram.h/mL in patients with cancer. The geometric mean oral clearance was 17.7 L/h. Lorlatinib oral clearance increased at steady-state compared to single dose, indicating autoinduction.

Distribution.

In vitro binding of lorlatinib to human plasma proteins is 66% with moderate binding to albumin and low binding to α1-acid glycoprotein.

Metabolism.

In humans, lorlatinib undergoes oxidation and glucuronidation as the primary metabolic pathways. In vitro data indicate that lorlatinib is metabolised primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.
In plasma, a benzoic acid metabolite (M8) of lorlatinib resulting from the oxidative cleavage of the amide and aromatic ether bonds of lorlatinib was observed as a major metabolite, accounting for 21% of the circulating radioactivity. The oxidative cleavage metabolite is pharmacologically inactive.

Elimination.

The plasma half life of lorlatinib after a single 100 mg dose was 23.6 hours. Following oral administration of a 100 mg radiolabeled dose of lorlatinib, a mean 47.7% of the radioactivity was recovered in urine and 40.9% of the radioactivity was recovered in faeces, with overall mean total recovery of 88.6%.
Unchanged lorlatinib was the major component of human plasma and faeces, accounting for 44% and 9.1% of total radioactivity in plasma and faeces, respectively. Less than 1% of unchanged lorlatinib was detected in urine.

Cardiac electrophysiology.

QT interval.

In Study B7461001, 2 patients (0.7%) had absolute Fridericia's correction QTc (QTcF) values > 500 msec, and 5 patients (1.8%) had a change in QTcF from baseline > 60 msec.
In addition, the effect of a single oral dose of lorlatinib (50 mg, 75 mg, and 100 mg) with and without 200 mg once daily itraconazole was evaluated in a 2 way crossover study in 16 healthy volunteers. No increases in the mean QTc interval were observed at the mean observed lorlatinib concentrations in this study.
In 295 patients who received lorlatinib at the recommended dose of 100 mg once daily in Study B7461001, no large mean increases from baseline in the QTcF interval (i.e. > 20 ms) were detected.

PR interval.

In 295 patients who received lorlatinib at the recommended dose of 100 mg once daily and had a ECG measurement in Study B7461001, the maximum mean change from baseline for PR interval was 16.4 ms (2 sided 90% upper CI: 19.4 ms). Among the 284 patients with PR interval < 200 ms, 14% had PR interval prolongation ≥ 200 ms after starting lorlatinib. The prolongation of PR interval occurred in a concentration dependent manner. Atrioventricular block occurred in 1.0% of patients.
For those patients who develop PR prolongation, dose modification may be required (see Section 4.2).

Special populations.

Hepatic impairment.

As lorlatinib is metabolised in the liver, hepatic impairment is likely to increase lorlatinib plasma concentrations. Clinical studies that were conducted excluded patients with AST or ALT > 2.5 x ULN, or if due to underlying malignancy, > 5.0 x ULN or with total bilirubin > 1.5 x ULN. Population pharmacokinetic analyses have shown that lorlatinib exposure was not clinically meaningfully altered in patients with mild hepatic impairment (n=50). No dose adjustments are recommended for patients with mild hepatic impairment (see Section 4.2). Lorlatinib has not been studied in patients with moderate or severe hepatic impairment.

Renal impairment.

Less than 1% of the administered dose is detected as unchanged lorlatinib in urine. Clinical studies excluded patients with serum creatinine > 1.5 x ULN or estimated CLcr < 60 mL/min. Population pharmacokinetic analyses have shown that lorlatinib exposure was not clinically meaningfully altered in patients with mild (n=103) or moderate (n=41) renal impairment (CLcr ≥ 30 mL/min). Based on a renal impairment study, no dose adjustments are recommended for patients with mild or moderate renal impairment [absolute eGFR based on Modification of Diet in Renal Disease Study equation (MDRD) derived eGFR (in mL/min/1.73 m2) x measured body surface area/1.73 ≥ 30 mL/min]. In this study, lorlatinib AUCinf increased by 41% in subjects with severe renal impairment (absolute eGFR < 30 mL/min) compared to subjects with normal renal function (absolute eGFR ≥ 90 mL/min). A reduced dose of Lorviqua is recommended in patients with severe renal impairment, e.g. a starting dose of 75 mg taken orally once daily (see Section 4.2).

Elderly (≥ 65 years).

Out of the 476 patients who received lorlatinib 100 mg orally once daily in Study B7461001 (N= 327) and Study B7461006 (N=149), 25% of patients were aged 65 years or older. Of the 215 patients in the efficacy population in Study B7461001, 17.7% of patients were aged 65 years or older, and of the 149 patients in the lorlatinib arm of the CROWN study, 40% were aged 65 years or older. No clinically relevant differences in safety or efficacy were observed between patients aged greater than or equal to 65 years of age and younger patients; no dose adjustments are recommended in elderly patients (see Section 4.2).

Gender, race, body weight, and phenotype.

Population pharmacokinetic analyses in patients with advanced NSCLC and healthy volunteers indicate that there are no clinically relevant effects of age, gender, race, body weight, or phenotypes for CYP3A5 and CYP2C19.

5.3 Preclinical Safety Data

Repeat dose toxicity.

The main toxicities observed were inflammation across multiple tissues (with increases in white blood cells), and changes in the pancreas (with increases in amylase and lipase), hepatobiliary system (with increases in liver enzymes), male reproductive system, cardiovascular system, kidneys and gastrointestinal tract, and peripheral nerves and the CNS (potential for cognitive functional impairment) (observed at as low as the human clinical exposure at 100 mg based on AUC for all toxicities). Changes in blood pressure and heart rate, and QRS and PR interval prolongation were also observed in animals after acute dosing (approximately 2.6 times the human clinical exposure at 100 mg after a single dose based on Cmax). All target organ findings with the exception of the hepatic bile duct hyperplasia were partially to fully reversible.

Genotoxicity.

Lorlatinib was not mutagenic in a bacterial reverse mutation (Ames) assay. Lorlatinib induced micronuclei via an aneugenic mechanism in human lymphoblastoid TK6 cells in vitro and in the bone marrow of rats.

Carcinogenicity.

Carcinogenicity studies have not been conducted with lorlatinib.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core contains.

Microcrystalline cellulose, calcium hydrogen phosphate, sodium starch glycollate, magnesium stearate.

Film-coating contains.

Hypromellose (E464), lactose monohydrate, macrogol 3350, triacetin, titanium dioxide (E171), iron oxide black (E172), iron oxide red (E172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the ARTG. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Aluminium foil blisters with aluminium foil backing containing 10 film coated tablets.

Pack sizes.

25 mg: 9 blister strips (90 tablets) per carton.
12 blister strips (120 tablets) per carton.
100 mg: 3 blister strips (30 tablets) per carton.
HDPE bottles with a polypropylene child resistant closure and desiccant canister. Each bottle contains 30 tablets.
Not all presentations may be marketed.

6.6 Special Precautions for Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

1454846-35-5.
Molecular weight: 406.4.
Aqueous solubility: decreases over the range pH 2.55 to pH 8.02 from 32.38 mg/mL to 0.17 mg/mL.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes