Consumer medicine information

Alecensa

Alectinib

BRAND INFORMATION

Brand name

Alecensa

Active ingredient

Alectinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Alecensa.

SUMMARY CMI

ALECENSA®

Consumer Medicine Information (CMI) summary

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

1. Why am I taking Alecensa?

Alecensa contains the active ingredient alectinib hydrochloride. Alecensa is used to treat patients who have a certain type of cancer - known as anaplastic lymphoma kinase (ALK)-fusion positive lung cancer. For more information, see Section 1. Why am I taking Alecensa? in the full CMI.

2. What should I know before I take Alecensa?

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

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I take Alecensa? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Alecensa 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 take Alecensa?

  • Alecensa is taken by mouth (orally) twice a day. Alecensa capsules should be swallowed whole with a glass of water and must not be opened or chewed. Alecensa should be taken with food.
  • If you get side effects, your doctor may change your dose, temporarily stop, or permanently stop treatment.

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

5. What should I know while taking Alecensa?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking Alecensa.
  • Ensure you are using effective contraception (men and women). Even if you stop treatment you should continue to use effective contraception for at least 1 week if you are a woman and 3 months if you are a man.
  • Tell your doctor straight away if you become pregnant.
  • Tell your doctor straight away if you experience any new or worsening symptoms or symptoms that concern you.
  • Alecensa may increase your sensitivity to sunlight so prolonged sun exposure should be avoided. Sunscreen and a lip balm with an SPF of 50 should be used whilst in sunlight.
Things you should not do
  • Do not stop taking this medicine, even if you feel well.
Driving or using machines
  • Be careful driving and/or operating heavy machinery until you know how Alecensa affects you.
Looking after your medicine
  • Store Alecensa in a cool, dry place where children cannot access it. Alecensa should be stored in a cool dry place where the temperature stays below 30°C.
  • If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

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

6. Are there any side effects?

Alecensa can cause side effects that you need to tell your doctor about straight away. Tell your doctor if you experience any side effects which concern you. Symptoms of serious side effects include difficulty breathing, shortness of breath, fever, yellowing of your skin or the whites of your eyes, unexplained muscle pain, decrease in urine, new or worsening swelling of legs, ankles or around the eyes, chest pain or pressure, severe abdominal or stomach pain. Some side effects might only be detected by blood tests or other tests. 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.



FULL CMI

ALECENSA® (ALI-SENS-A)

Active ingredient(s): alectinib hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about taking Alecensa. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking Alecensa.

Where to find information in this leaflet:

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

1. Why am I taking Alecensa?

Alecensa contains the active ingredient alectinib hydrochloride. Alecensa is a cancer medicine. In patients whose cancer is due to an altered anaplastic lymphoma kinase (ALK) gene, the change in the gene causes the body to make an abnormal protein called an ALK fusion protein, which can lead to uncontrolled cell growth and cancer. Alecensa blocks the action of ALK fusion proteins and may help to slow or stop your cancer from growing. It may also help to shrink your cancer.

Alecensa is used to treat adults who have non-small cell lung cancer, caused by ALK genes that is advanced or spread to other parts of the body (metastatic).

2. What should I know before I take Alecensa?

Warnings

Do not take Alecensa if:

  • you are allergic to alectinib hydrochloride, or any of the ingredients listed at the end of this leaflet in Section 7 Product details

Some symptoms of an allergic reaction 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

It is not known if Alecensa is safe and effective in children younger than 18 years of age.

Check with your doctor if you:

  • take any medicines for any other condition
  • have or have had any of the following medical conditions:
    - liver problems - your doctor will do blood tests before treatment to check your liver function
    - you cannot tolerate lactose, or you have an inherited problem called galactose intolerance, congenital lactase deficiency or glucose-galactose malabsorption;
    - if you have ever had stomach or intestine problems such as holes (perforation);
    - or if you have conditions causing inflammation inside the abdomen (diverticulitis);
    - if you have spread of cancer inside the abdomen (metastasis)

It is possible that Alecensa may increase the risk of developing holes in the wall of your gut.

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

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Your doctor will perform a pregnancy test before you start treatment with Alecensa.

This medicine is not recommended for use during pregnancy unless absolutely necessary. Avoid becoming pregnant while being treated with this medicine as it may harm your unborn baby. Your doctor will discuss with you the potential risks of taking Alecensa during pregnancy.

Breastfeeding:

It is not known if Alecensa passes into your breast milk. Do not breastfeed during treatment and for one week after your final dose of Alecensa.

Contraception in females:

You should avoid becoming pregnant while taking this medicine. If you are able to have children, you must use highly effective contraception (for example, double-barrier contraception such as condom and diaphragm) while on treatment and for at least one week after stopping treatment.

Contraception in males:

Males with female partners of childbearing potential must use effective contraception during treatment and for at least 3 months after completion of treatment.

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

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.

Alecensa may interfere with some medicines. These include some medicines with a narrow therapeutic index (meaning medicines that need tight control of the dose to produce the desired effects without causing severe or fatal problems). These include:

  • digoxin, used to treat heart disease
  • dabigatran, used to prevent or treat blood clots
  • methotrexate, used to treat rheumatoid arthritis and some cancers

These medicines may be affected by Alecensa or may affect how well 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 Alecensa.

4. How do I take Alecensa?

Your healthcare provider will perform a test to make sure that Alecensa is right for you.

How much to take

  • Follow the instructions provided by your doctor and take Alecensa until your doctor tells you to stop. The recommended dose is 600 mg (4 capsules) taken by mouth, twice daily.

When and how to take Alecensa

  • Alecensa is usually taken twice a day with food.
  • Take 4 capsules in the morning (i.e. with breakfast), then 4 capsules in the evening (i.e. with dinner).
  • Take your medicine at about the same times each day.
    Taking it at the same time each day will have the best effect. It will also help you remember when to take it.
  • Alecensa capsules should be swallowed whole with a glass of water and must not be opened, chewed or dissolved.
  • Do not change your dose or stop taking Alecensa unless your healthcare provider tells you to. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with Alecensa.

If you forget to take Alecensa

Alecensa should be taken regularly at the same time each day. If you miss your dose at the usual time, or if you vomit after taking a 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.

This may increase the chance of you getting an unwanted side effect.

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 Alecensa

If you think that you have taken too much Alecensa, 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 taking Alecensa?

Things you should do

Tell all doctors, dentists, and pharmacists who treat you that you are taking Alecensa.

If you become pregnant while taking this medicine, or within 1 week of stopping this medicine, tell your doctor immediately. Ensure you are using effective contraception (see further details above under Section 2).

Avoid prolonged exposure to the sun while you are taking Alecensa and for at least 7 days after you stop. Apply sunscreen and a lip balm with a SPF of 50 or higher and cover your arms, legs and head to reduce exposure to sunlight. Alecensa may increase your sensitivity to sunlight.

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

Your doctor will do blood tests and other tests from time to time to monitor your progress and check for side effects. If necessary, your doctor may decide to reduce your dose, temporarily interrupt your treatment or stop it altogether.

Things you should not do

  • Do not take Alecensa to treat any other complaints unless your doctor tells you to
  • Do not stop taking your medicine or changing the amount you take without checking with your doctor
  • Do not give your medicine to anyone else, even if they have the same condition as you

Driving or using machines

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

Alecensa may cause problems with vision or slowing of the heartbeat or low blood pressure that can lead to dizziness or fainting in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

If you experience any of these problems and they continue or get worse, talk to your doctor

Looking after your medicine

Store Alecensa at room temperature (below 30°C) in a dry place away from moisture, heat or sunlight; for example, do not store it:

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

Keep your capsules inside the original package until it is time to take them. If you take the capsules out of the package they may not keep well.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not take this medicine after the expiry date which is stated on the blister pack and outer carton after "EXP". The expiry date refers to the last day of that month.

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.

Less serious side effects

Less serious side effectsWhat to do
Gut-related:
  • Diarrhoea and/or constipation
  • Nausea and/or vomiting
Skin-related:
  • Rash
Eye-related:
  • blurred or impaired vision, black dots or white spots in your vision, double vision
Other:
  • tiredness
  • dizziness
  • headache
  • sensitivity to sunlight
  • inflammation in your mouth
  • change in sense of taste
  • weight gain
  • swelling of hands, feet, legs or around the eyes
Speak to your doctor if you have any of these less serious side effects and they worry you, or if they do not go away or get worse.

Serious side effects

Serious side effectsWhat to do
Gut-related:
  • severe stomach or abdominal pain, fever, chills, sickness, vomiting, or abdominal rigidity or bloating. These could be symptoms of a hole in the wall of your gut, and could happen even after you stop taking Alecensa
Breathing-related:
  • shortness of breath or difficulty breathing
  • cough and/or fever
Liver-related:
  • yellowing of your skin or the whites of your eyes
Heart-related:
  • slow heart beat (bradycardia)
Muscle-related:
  • new or worsening signs and symptoms of muscle problems, including unexplained muscle pain that does not go away, tenderness or weakness
Kidney-related:
  • decrease in urine, confusion, new or worsening swelling of legs, ankles or around the eyes, tiredness, nausea, chest pain or pressure
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital 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 Alecensa contains

Active ingredient
(main ingredient)		alectinib hydrochloride
Other ingredients
(inactive ingredients)

lactose monohydrate, hyprolose, sodium lauryl sulfate, carmellose calcium, magnesium stearate

Capsule shell: carrageenan, potassium chloride, titanium dioxide, carnauba wax, maize starch, hypromellose

Printing ink: iron oxide red (E172), iron oxide yellow (E172), indigo carmine aluminium lake, carnauba wax, shellac, glyceryl monooleate

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

What Alecensa looks like

Alecensa 150 mg capsules are white and are printed with "ALE" on the cap and "150 mg" printed on the body in black ink.

The capsules are provided in blisters and are available in multipacks containing 224 hard capsules (4 packs of 56).

(AUST R 272115).

Who distributes Alecensa

Alecensa is distributed in Australia by:

Roche Products Pty Ltd
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
Medical enquiries: 1800 233 950

This leaflet was prepared in November 2023.

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Alecensa

Active ingredient

Alectinib

Schedule

S4

 

1 Name of Medicine

Alecensa (alectinib) 150 mg hard capsules.

2 Qualitative and Quantitative Composition

Each capsule contains 161.3 mg alectinib hydrochloride equivalent to 150 mg alectinib.
Alectinib hydrochloride is a tyrosine kinase inhibitor for oral administration. The molecular formula is C30H35ClN4O2 HCl. The molecular weight is 482.62 g/mol (free base form) and 519.08 g/mol (hydrochloride salt). Alectinib hydrochloride is described chemically as: 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. Alectinib HCl is a white to yellow white powder or powder with lumps, with a pKa of 7.05 (base). It has low solubility in aqueous buffers across the pH range, and low to high solubility in organic solvents.

Excipients with known effect.

Each capsule contains 33.7 mg lactose monohydrate and 6 mg sodium (as sodium lauryl sulfate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White hard capsule of 19.2 mm length with "ALE" printed in black ink on the cap and "150 mg" printed in black ink on the body.

4 Clinical Particulars

4.1 Therapeutic Indications

Alecensa is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC).

4.2 Dose and Method of Administration

A validated ALK assay is required for the selection of ALK-positive NSCLC patients. ALK positive NSCLC status should be established prior to initiation of Alecensa therapy.

Dose.

The recommended dose of Alecensa is 600 mg (four 150 mg capsules) given orally, twice daily with food (total daily dose of 1200 mg).

Duration of treatment.

It is recommended that patients are treated with Alecensa until disease progression or unacceptable toxicity.

Delayed or missed doses.

Advise patients that if a dose of Alecensa is missed, or if the patient vomits after taking a dose of Alecensa, patients should be advised not to take an extra dose, but to take the next dose at the regular time.

Dose modifications.

Management of adverse events may require temporary interruption, dose reduction, or discontinuation of treatment with Alecensa. The dose of Alecensa should be reduced in steps of 150 mg twice daily based on tolerability (Table 1). Dose modification guidelines for specific adverse events are provided in Table 2 (also see Section 4.4 Special Warnings and Precautions for Use). Alecensa treatment should be permanently discontinued if patients are unable to tolerate the 300 mg twice daily dose.

Special populations.

Elderly.

No dose adjustment of Alecensa is required in patients ≥ 65 years of age.

Paediatric population.

The safety and efficacy of Alecensa in children and adolescents below 18 years of age have not been established.

Renal impairment.

No dose adjustment is required in patients with renal impairment (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

No starting dose adjustment is required in patients with underlying mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Patients with underlying severe hepatic impairment (Child-Pugh C) should receive a starting dose of 450 mg given orally twice daily (total daily dose of 900 mg). For all patients with hepatic impairment, appropriate monitoring (e.g. markers of liver function) is advised (see Section 4.4 Special Warnings and Precautions for Use).

Method of administration.

Alecensa hard capsules should be swallowed whole and must not be opened or dissolved. They must be taken with food.

4.3 Contraindications

Alecensa is contraindicated in patients with a known hypersensitivity to alectinib or any of the excipients listed, see Section 6.1.

4.4 Special Warnings and Precautions for Use

Gastrointestinal perforation.

Cases of gastrointestinal perforation have been reported in patients at increased risk (e.g. history of diverticulitis, metastases to the gastrointestinal tract, concomitant use of medicinal product with a recognised risk of gastrointestinal perforation) and alectinib should be used with caution.
Patients should be informed of the signs and symptoms of gastrointestinal perforations and advised to seek rapid medical attention in case of occurrence. Discontinuation of alectinib in patients who develop gastrointestinal perforation should be considered.

Interstitial lung disease (ILD)/pneumonitis.

Cases of severe ILD/pneumonitis have been reported with Alecensa in clinical trials and post-marketing, including severe ILD/pneumonitis (grade 3) in one patient (0.4%) out of 253 patients exposed in the phase I/II clinical trials (studies 1 and 2). In study 3, 2 patients (1.3%) treated with Alecensa had an ILD event, neither of which was severe (grade ≥ 3). There were no fatal cases of ILD in any of the clinical trials.
Promptly investigate worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g. dyspnoea, cough and fever) in any patient taking Alecensa. Immediately withhold treatment with Alecensa in patients diagnosed with ILD/pneumonitis and permanently discontinue it if no other potential causes of ILD/pneumonitis are identified (see Section 4.2 Dose and Method of Administration).

Hepatotoxicity.

In the pivotal clinical trials, elevations of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin (including cases of blood bilirubin increased, hyperbilirubinaemia and bilirubin conjugated increased) were commonly reported as adverse events. In phase I/II clinical trials (studies 1 and 2), the incidences of these events were 14%, 16% and 17%, respectively. In the phase III clinical trial (study 3) these events were reported in 15%, 14% and 21%, respectively. The events were generally low grade, transient rises that occurred within the first three months of treatment and resolved with temporary interruption of Alecensa treatment or dose reduction. Treatment interruption for ALT, AST or bilirubin rise occurred in 3.2%, 1.2% and 5.1% of patients, respectively, in phase I/II clinical trials (studies 1 and 2) and in 2.6%, 2.0% and 2.6%, respectively, in the phase III clinical trial (study 3). In the same studies, dose reduction for ALT, AST or bilirubin rise occurred in 0.8%, 1.6% and 2.8% of patients in studies 1 and 2 and in 2.0%, 2.6% and 4.6% in study 3, respectively.
Higher grade elevations of ALT and AST (greater than 5-fold the ULN) and bilirubin elevations of more than 3 times the ULN were reported. In phase I/II clinical trials (studies 1 and 2), elevations of ALT and AST (greater than 5-fold the ULN) and bilirubin (greater than 3-fold the ULN) occurred in 3.2%, 2.8% and 3.2% of patients, respectively. In the same studies, ALT, AST and bilirubin elevations led to withdrawal from treatment with Alecensa in 1.6%, 1.2% and 1.6% of patients, respectively.
In the phase III clinical trial (study 3), elevation of AST greater than 5 times the ULN occurred in 6.2% and elevation of ALT greater than 5 times the ULN occurred in 6.1% of patients treated with Alecensa, respectively. Elevations of bilirubin greater than 3 times the ULN occurred in 5.5% of patients who received Alecensa treatment. The majority (56% of the patients with hepatic transaminase elevations and 69% of the patients with bilirubin elevations) of these events occurred during the first 3 months of treatment. Two patients (1.3%) discontinued Alecensa due to grade 3-4 adverse events of elevated hepatic transaminases. Alecensa treatment was discontinued due to a grade 3 adverse event of elevated bilirubin in 1 patient (0.7%).
In studies 1, 2 and 3, two patients with grade 3-4 AST/ALT elevations had documented drug induced liver injury by liver biopsy. In addition, one patient experienced a grade 4 adverse event of drug-induced liver injury and another patient experienced concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase (grade 4 hepatotoxicity).
Test for liver function (including ALT, AST, and total bilirubin) at baseline and then every 2 weeks during the first 3 months of treatment. Test periodically during treatment thereafter, with more frequent testing in patients who develop transaminase and bilirubin elevations. Based on the severity of the reaction, withhold Alecensa and resume at a reduced dose, or permanently discontinue Alecensa as described, see Section 4.2.

Bradycardia.

Symptomatic bradycardia can occur with Alecensa. In the phase I/II clinical trials (studies 1 and 2), there were 14 cases of sinus bradycardia (5.5%) and 7 cases of bradycardia (2.8%), some of which were symptomatic. None were severe or serious. Of 221 patients in studies 1 and 2 treated with Alecensa who had serial ECGs available, 20% had post-dose heart rates slower than 50 beats per minute (bpm). In study 3, cases of bradycardia were reported in 11% of patients treated with Alecensa (see Section 4.8 Adverse Effects (Undesirable Effects), Table 3). Of the 144 patients treated with Alecensa for whom serial ECGs were available, 15% had heart rates of less than 50 bpm.
Heart rate and blood pressure should be monitored regularly. No dose modification is required for asymptomatic bradycardia. If symptomatic or life-threatening bradycardia occurs, adjust Alecensa treatment as described, see Section 4.2.

Severe myalgia and creatine phosphokinase (CPK) elevation.

Myalgia/musculoskeletal pain were reported very commonly in patients treated with Alecensa in clinical trials. In phase I/II clinical trials (studies 1 and 2), myalgia/musculoskeletal pain was reported in 30.8% of patients treated with Alecensa. The majority of these events were grades 1 or 2 and three patients (1.2%) had a grade 3 event. The Alecensa dose was modified for two patients (0.8%), due to these events. Elevations of CPK occurred in 46% of 219 patients who had their CPK measured in studies 1 and 2, and ten of these patients (5.0%) had grade 3 elevations. Dose modifications for elevation of CPK occurred in 4.0% of patients.
Myalgia or musculoskeletal pain occurred in 23% of patients treated with Alecensa in study 3. No patient experienced a grade ≥ 3 adverse event, discontinued study treatment or had dose modifications due to these adverse events. CPK elevations occurred in 37% of 129 Alecensa-treated patients with available CPK laboratory data in study 3. Grade 3 elevations of CPK occurred in 3.1% of patients treated with Alecensa. Dose modifications for elevation of CPK occurred in 1.3% of patients treated with Alecensa.
Median time to grade 3 CPK elevation was 14 days in the pivotal phase I/II trials (studies 1 and 2). Median time to grade 3 CPK elevation was 27.5 days in the pivotal phase III clinical trial (study 3).
Advise patients to report any unexplained muscle pain, tenderness, or weakness. Assess CPK levels every fortnight for the first month of treatment and as clinically indicated in patients reporting symptoms. Based on the severity of the CPK elevation, withhold Alecensa, then resume or reduce dose (see Section 4.2 Dose and Method of Administration).

Haemolytic anaemia.

Haemolytic anaemia has been reported with Alecensa (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing). If haemoglobin concentration is below 100 g/L and haemolytic anaemia is suspected, withhold Alecensa and initiate appropriate laboratory testing. If haemolytic anaemia is confirmed, resume at a reduced dose upon resolution or permanently discontinue Alecensa (see Section 4.2 Dose and Method of Administration).

Photosensitivity.

Photosensitivity and/or sunburn occurred in 30 (11.9%) patients exposed to Alecensa in the phase I/II clinical trials and in 8 (5.3%) patients treated with Alecensa in the phase III trial. Study participants were advised to avoid sun exposure and to use broad-spectrum sunscreen. All events were grade 1 or 2 severity except for one non-serious grade 3 event.
Advise patients that they should avoid prolonged sun exposure and use a broad-spectrum Ultraviolet A (UVA)/Ultraviolet B (UVB) sunscreen and lip balm (both SPF ≥ 50) whilst taking Alecensa and for at least 7 days after discontinuation.

Use in hepatic impairment.

As elimination of alectinib is predominantly through metabolism in the liver, hepatic impairment may increase the plasma concentration of alectinib and/or its major metabolite M4. Based on a population pharmacokinetic analysis, alectinib and M4 exposures were similar in patients with mild hepatic impairment and normal hepatic function.
Following administration of a single oral dose of 300 mg alectinib in subjects with severe (Child-Pugh C) hepatic impairment, alectinib Cmax was the same and AUCinf was 2.2-fold higher compared with the same parameters in matched healthy subjects. M4 Cmax and AUCinf was 39% and 34% lower respectively, resulting in a combined exposure of alectinib and M4 (AUCinf) 1.8-fold higher in patients with severe hepatic impairment compared with matched healthy subjects.
The hepatic impairment study also included a group with moderate (Child-Pugh B) hepatic impairment, and a modestly higher alectinib exposure was observed in this group compared with matched healthy subjects. The subjects in the Child Pugh B group however did in general not suffer from abnormal bilirubin, albumin or prothrombin time, indicating that they may not be fully representative of moderately hepatically impaired subjects with decreased metabolic capacity.

Use in renal impairment.

Mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min) had no clinically meaningful effect on the systemic exposure of alectinib and the active metabolite M4. No dose adjustment is required in mild to moderate renal impairment. Negligible amounts of alectinib and M4 are excreted unchanged in urine (< 0.2% of the dose). The pharmacokinetics of alectinib has not been studied in patients with severe renal impairment, however due to the negligible renal clearance of alectinib, no dose adjustment is required in severe renal impairment.

Use in the elderly.

Age does not have an effect on Alecensa exposure (see Section 5.2 Pharmacokinetic Properties). However, clinical studies of Alecensa did not include sufficient number of subjects aged 65 and older to determine whether they respond differently from younger subjects.

Paediatric use.

The safety and efficacy of Alecensa in children and adolescents below 18 years of age have not been established (also see Section 5.3 Preclinical Safety Data).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of alectinib on other medicines.

CYP substrates.

In vitro studies suggest that alectinib and M4 do not inhibit CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6. No clinically meaningful effect on the exposure of midazolam (a sensitive CYP3A substrate) or repaglinide (a sensitive CYP2C8 substrate) is expected following co-administration with Alecensa. No dose adjustment is required for co-administered CYP3A substrates.

P-gp and BCRP substrates.

In vitro studies suggest that alectinib and M4 inhibit P-gp and BCRP. Therefore, alectinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp or BCRP transporters (the increase in exposure is not expected to be more than 2-fold). Appropriate monitoring is recommended when Alecensa is co-administered with P-gp or BCRP substrates with narrow therapeutic index (e.g. digoxin, dabigatran, methotrexate).

Other transporters.

Alectinib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 transport activity in vitro.

Effects of other medicines on alectinib.

CYP3A inducers.

Co-administration of multiple oral doses of 600 mg rifampicin once daily, a strong CYP3A inducer, with a single oral dose of 600 mg alectinib exhibited a minor effect on combined exposure of alectinib and M4 (geometric mean ratio with/without rifampicin [90% confidence interval]: Cmax 0.96 [0.88 - 1.05], AUCinf 0.82 [0.74 - 0.90]). Therefore, no dose adjustments are required when Alecensa is co-administered with CYP3A inducers.

CYP3A inhibitors.

Co-administration of multiple oral doses of 400 mg posaconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of 300 mg alectinib had a minor effect on combined exposure of alectinib and M4 (geometric mean ratio with/without posaconazole [90% confidence interval]: Cmax 0.93 [0.81 - 1.08], AUCinf 1.36 [1.24 - 1.49]). Therefore, no dose adjustments are required when Alecensa is co-administered with CYP3A inhibitors.

Medicinal products that increase gastric pH.

Although the aqueous solubility of alectinib in vitro is pH dependent, a dedicated clinical drug-drug interaction study with 40 mg esomeprazole once daily, a proton pump inhibitor, demonstrated no clinically relevant effect on the combined exposure of alectinib and M4. Therefore, no dose adjustments are required when Alecensa is co-administered with proton pump inhibitors or other drugs which raise gastric pH (e.g. H2 receptor antagonists or antacids).

Effect of transporters on alectinib disposition.

Based on in vitro data, alectinib is not a substrate of P-gp. Alectinib and M4 are not substrates of BCRP or organic anion-transporting polypeptide (OATP) 1B1/B3. In contrast, M4 is a substrate of P-gp. Alectinib inhibits P-gp, and therefore, it is not expected that co-medication with P-gp inhibitors has a relevant effect on M4 exposure.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No fertility-specific studies of alectinib in animals have been performed.

Contraception in males and females.

Alecensa may cause fetal harm when administered to a pregnant woman (see below). Advise females of reproductive potential to avoid pregnancy by using highly effective contraception during treatment with Alecensa and for at least 1 week after the final dose.
Based on genotoxicity findings (see Section 5.3 Preclinical Safety Data), advise males with female partners of reproductive potential to use highly effective contraception during treatment with Alecensa and for 3 months following the final dose.
(Category D)
In animal studies, a maternal dose of alectinib (27 mg/kg/day) equivalent to 2.7-times the recommended human dose of 600 mg twice-daily (based on AUC) caused embryo-fetal loss (miscarriage), visceral malformation (retro-oesophageal subclavian) and skeletal variations (an increase in full supernumerary ribs and a corresponding decrease in short supernumerary ribs) in pregnant rabbits. The same dose given to pregnant rats (4 times the clinical AUC) resulted in total litter loss. Alectinib at 9 mg/kg/day (2.5 times the clinical AUC) caused small fetuses and fetal abnormalities (dilated ureter, thymic cord, small ventricle and thin ventricle wall of the heart, and decreased number of sacral and caudal vertebrae).
Based on animal studies and its mechanism of action, Alecensa may cause fetal harm if taken during pregnancy. No clinical studies of Alecensa in pregnant women have been performed.
Advise a pregnant woman of the potential harm to the fetus.
Advise patients that they must inform their healthcare provider of a known or suspected pregnancy.
The use of Alecensa during labour and delivery has not been established.
 There are no data on the presence of alectinib or its metabolites in human milk, the effects of alectinib on the breastfed infant, or its effects on milk production. Because of the potential for serious adverse reactions from alectinib in breastfed infants, advise a lactating woman not to breastfeed during treatment with Alecensa and for 1 week after the final dose.

4.7 Effects on Ability to Drive and Use Machines

No studies of the effects on the ability to drive and to use machines have been performed.
Caution should be exercised when driving or operating machines as patients may experience symptomatic bradycardia (e.g. syncope, dizziness, hypotension) or vision disorders while taking Alecensa (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

The following adverse events of specific concern are discussed in detail, see Section 4.4: interstitial lung disease (ILD)/pneumonitis; hepatotoxicity; bradycardia; severe myalgia and creatine phosphokinase (CPK) elevation; photosensitivity.
The safety profile of Alecensa was generally consistent across the phase III clinical trial (study 3) and the pivotal phase I/II trials (studies 1 and 2); however, relevant differences between studies are described, see Section 4.4.

Clinical trials.

Patients not previously treated systemically for advanced or metastatic NSCLC.

The safety of Alecensa 600 mg twice daily compared to crizotinib 250 mg twice daily was evaluated in 152 and 151 patients with ALK-positive NSCLC, respectively, in the phase III clinical trial, study 3 (ALEX). The median duration of exposure to Alecensa and crizotinib was 17.9 and 10.7 months, respectively. Patients presenting with baseline symptomatic bradycardia were not studied in this trial.
Serious adverse reactions occurred in 28% and 29% of patients treated with Alecensa and crizotinib, respectively. The most frequently reported serious adverse reactions were pneumonia (3.3%) and acute kidney injury (2.6%) for patients treated with Alecensa, and pneumonia, pneumonitis and elevated ALT (2.6% each) for patients treated with crizotinib. Grade ≥ 3 adverse events were reported for 41% of patients in the Alecensa arm and 50% in the crizotinib arm. Fatal adverse events occurred in both treatment arms: 5 (3.3%), all unrelated in the Alecensa arm, and 7 (4.6%), 2 related in the crizotinib arm.
Permanent treatment discontinuation for adverse reactions occurred in 11% of patients treated with Alecensa, and in 13% of crizotinib-treated patients. Acute kidney injury was the most commonly reported adverse drug reaction leading to study drug discontinuation in the Alecensa arm (2.0%) and elevated ALT (5.3%), AST (4.0%) and pneumonitis (2.6%) in the crizotinib arm. Dose modifications (dose reductions and drug interruption, respectively) were required in 16% and 19% of patients in the Alecensa arm and in 21% and 25% in the crizotinib arm, respectively. The most frequent adverse reactions that led to dose modifications in the Alecensa arm were pneumonia, elevation in ALT and AST and in the crizotinib arm were elevated ALT, AST, neutropenia and vomiting.
Additional adverse drug reactions in patients treated with Alecensa compared to crizotinib respectively include weight increased (9.9% vs 0%), photosensitivity reaction (5.3% vs 0%), stomatitis (3.3% vs 2.6%, which includes cases of stomatitis and mouth ulceration), interstitial lung disease (1.3% vs. 6.0%, which includes cases of interstitial lung disease and pneumonitis), and hepatotoxicity (1.4% vs. 0.7%, which includes cases of drug-induced liver injury, 0.7% vs 0.7, and hepatotoxicity).
Table 4 summarises treatment-emergent shifts in laboratory abnormalities with Alecensa in study 3 (ALEX).

Crizotinib pre-treated patients.

The safety of Alecensa has been evaluated in two phase I/II clinical trials (studies 1 and 2) in 253 patients with ALK-positive non-small cell lung cancer (NSCLC) treated with the recommended dose of 600 mg twice daily. Due to the single-arm design of these trials, no control adverse event data is available, and treatment emergent adverse event data is presented below. The median duration of exposure to Alecensa was 11 months (range 0-35 months) with 169 patients (67%) exposed for more than 6 months, and 123 patients (49%) for more than 12 months. The characteristics of the population were: median age 53 years, 86% aged less than 65 years, 55% female, 74% White, 18% Asian, 96% NSCLC adenocarcinoma histology, 98% never or former smokers, 91% with ECOG performance status 0 or 1, and 78% had prior chemotherapy treatment.
The most common adverse events (≥ 20%) were fatigue (44%, includes fatigue and asthenia), constipation (36%), oedema (34%, includes peripheral, generalised, eyelid, periorbital), myalgia (31%, includes myalgia and musculoskeletal pain), nausea (22%), cough (21%), rash (20%, includes rash, maculopapular rash, acneiform dermatitis, erythema, generalised rash, papular rash, pruritic rash, and macular rash) and headache (20%).
Serious adverse events occurred in 22% of patients. The most frequent reported serious adverse events were pulmonary embolism (1.2%), dyspnoea (1.2%) and hyperbilirubinaemia (1.2%). Fatal adverse reactions occurred in 2.8% of patients and included haemorrhage (0.8%), intestinal perforation (0.4%), dyspnoea (0.4%), pulmonary embolism (0.4%), endocarditis (0.4%) and unknown adverse reaction (0.4%).
Adverse events led to permanent discontinuation of Alecensa in 6% of patients, most frequently due to hyperbilirubinaemia (1.6%), increased ALT levels (1.6%), and increased AST levels (1.2%). At least one dose reduction or interruption was required for 33% of patients initiating treatment at the recommended dose, and the median time to first dose reduction or interruption was 56 days. The most frequent adverse reactions that led to dose changes were elevations in bilirubin (6.3%), CPK (4.3%), ALT (4.0%) or AST (2.8%), and vomiting (3.2%).
Table 5 summarises the most common treatment-emergent adverse events (≥ 10% any grade and ≥ 2% grade 3-5) occurring in patients who received Alecensa (600 mg twice daily) in studies 1 and 2.
Table 6 summarises the most common treatment-emergent shifts in key laboratory abnormalities occurring in patients who received Alecensa in studies 1 and 2.

Post-marketing.

The adverse drug reaction of increased alkaline phosphatase was reported with Alecensa in the post-marketing setting. Cases of increased alkaline phosphatase have been reported in Alecensa clinical trials (7.5% in patients treated with Alecensa in phase I/II clinical trials - studies 1 and 2).
The adverse drug reaction of haemolytic anaemia was reported with Alecensa in the post-marketing setting. Cases of haemolytic anaemia have been reported in the Alecensa clinical trial BO29554 (BFAST).

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 https://www.tga.gov.au/reporting-problems.

4.9 Overdose

No experience with overdosage is available from the pivotal clinical trials and there is no specific antidote for overdosage with Alecensa. Patients who experience overdose should be closely supervised and supportive care instituted. Alectinib is > 99% bound to plasma proteins and haemodialysis is likely to be ineffective in the treatment of overdose.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Alectinib is a tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and Rearranged during Transfection (RET) tyrosine kinase.
In nonclinical studies, alectinib inhibits ALK tyrosine kinase activity, leading to blockage of downstream signalling pathways including STAT3 and PI3K/AKT, and inhibits proliferation of cancer cells harbouring ALK fusion proteins.
Alectinib demonstrated in vitro and in vivo activity against mutant forms of ALK, including some that have been identified in non-small cell lung cancer (NSCLC) tumours in patients who progressed on crizotinib. The major active metabolite of alectinib (M4) showed similar in vitro potency and activity.
Administration of alectinib to mice implanted with ALK-rearranged tumour cell line xenografts, including some that received intracranial xenografts, resulted in antitumour activity and prolonged survival.

Clinical trials.

Patients not previously treated systemically for advanced or metastatic NSCLC. The safety and efficacy of Alecensa were studied in a global randomised phase III open label clinical trial [study 3 (ALEX)] in ALK-positive NSCLC patients not previously treated systemically for advanced or metastatic NSCLC. Central testing for ALK protein expression positivity of tissue samples from all patients by Ventana anti-ALK (D5F3) immunohistochemistry (IHC) was required before randomisation into the study. Retrospective ALK testing using the Vysis fluorescence in situ hybridisation (FISH) assay was also performed.
A total of 303 patients were included in the phase III trial, 151 patients randomised to the crizotinib arm and 152 patients randomised to the Alecensa arm receiving Alecensa orally, at the recommended dose of 600 mg twice daily.
ECOG performance status (0/1 vs. 2), race (Asian vs. non-Asian), and CNS metastases at baseline (yes vs. no) were stratification factors for randomisation. The primary endpoint of the trial was to demonstrate superiority of Alecensa versus crizotinib based on Progression Free Survival (PFS) as per investigator assessment using RECIST 1.1. Baseline demographic and disease characteristics for Alecensa were median age 58 years (54 years for crizotinib), 55% female (58% for crizotinib), 55% non-Asian (54% for crizotinib), 61% with no smoking history (65% for crizotinib), 93% ECOG performance status of 0 or 1 (93% for crizotinib), 97% Stage IV disease (96% for crizotinib), 90% adenocarcinoma histology (94% for crizotinib), 40% CNS metastases at baseline (38% for crizotinib) and 17% having received prior CNS radiation (14% for crizotinib).
The trial met its primary endpoint at the primary analysis. Efficacy data are summarised in Table 7 and the Kaplan-Meier curves for investigator and Independent Review Committee (IRC)-assessed PFS are shown in Figures 1 and 2.
The magnitude of PFS benefit was consistent for patients with CNS metastases at baseline (HR = 0.40, 95% CI: 0.25-0.64, median PFS for Alecensa = NE, 95% CI: 9.2-NE, median PFS for crizotinib = 7.4 months, 95% CI: 6.6-9.6) and without CNS metastases at baseline (HR = 0.51, 95% CI: 0.33-0.80, median PFS for Alecensa = NE, 95% CI: NE, NE, median PFS for crizotinib = 14.8 months, 95% CI:10.8-20.3), indicating benefit of Alecensa over crizotinib in both subgroups.
Crizotinib pre-treated patients. The use of Alecensa in the treatment of ALK-positive NSCLC patients previously treated with crizotinib was investigated in two multicentre, open-label, single-arm studies, referred to in this document as study 1 and study 2. Both studies enrolled patients with locally advanced or metastatic ALK-positive NSCLC, who had progressed on crizotinib, with documented ALK-positive NSCLC based on an FDA-approved test, and ECOG performance status of up to 2. Eligibility criteria permitted enrolment of patients with prior chemotherapy and prior CNS radiotherapy provided that CNS metastases were stable for at least two weeks.
All patients received Alecensa 600 mg orally twice daily. The primary endpoint in both studies was objective response rate (ORR) in the overall population, according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) as evaluated by an Independent Review Committee (IRC). Additional outcome measures as evaluated by the IRC included duration of response (DOR), CNS ORR, and CNS DOR. Study 2 included as co-primary endpoint evaluation of ORR by IRC using RECIST v1.1 in patients with prior exposure of cytotoxic chemotherapy treatments.
Study 1 was conducted in North America and included 87 patients in the phase II part of the study. Baseline demographic and disease characteristics in study 1 were median age 54 years (range 29 to 79 years, 18% ≥ 65 years), 84% White and 8% Asian, 55% female, 35% ECOG performance status 0 and 55% ECOG performance status 1, 100% never or former smokers, 99% Stage IV, 94% adenocarcinoma, and 74% prior chemotherapy. The most common sites of extra-thoracic metastasis included 60% CNS (of whom 65% had received CNS radiation), 43% lymph nodes, 36% bone, and 34% liver.
Study 2 was conducted internationally and included 138 patients in the phase II part of the study. Baseline demographic and disease characteristics in study 2 were median age 52 years (range 22 to 79 years, 10% ≥ 65 years), 67% White and 26% Asian, 56% female, 32% ECOG performance status 0 and 59% ECOG performance status 1, 98% never or former smokers, 99% Stage IV, 96% adenocarcinoma, and 80% prior chemotherapy. The most common sites of extra-thoracic metastasis included 61% CNS (of whom 73% had received CNS radiation), 51% bone, 38% lymph nodes, and 30% liver.

Efficacy.

Efficacy results from studies 1 and 2 in all treated patients are summarised in Table 8. The median duration of follow-up was 17 months in study 1 and 21 months in study 2 for both IRC and Investigator assessments. According to the IRC, all responses were partial responses. According to Investigator assessment, 2 patients and 3 patients achieved a complete response in study 1 and study 2, respectively.

CNS efficacy.

Results of ORR and DOR for CNS metastases in a subgroup of 50 patients (pooled from both studies 1 and 2) who had measurable CNS lesions at baseline according to RECIST v1.1 are summarised in Table 9. Thirty-four (68%) patients with measurable CNS lesions had received prior brain radiation, including 25 (50%) who had completed radiation treatment at least 6 months before starting treatment with Alecensa. Responses were observed irrespective of prior brain radiation status.

Quality of life (QoL).

In study 1, 79 patients (91%) completed questionnaires at baseline and during treatment to assess QoL. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and Lung Cancer subscale (LC13) were used, in which clinically meaningful improvement is defined as a change from baseline of ≥ 10 points. A median change of 16.7 points was seen in the 'Global Health Status' domain (during weeks 6 to 30). There were no detriments meeting the threshold for clinically meaningful change in any of the subscales assessed.

5.2 Pharmacokinetic Properties

The pharmacokinetic (PK) parameters for alectinib and its major active metabolite (M4) have been characterised in healthy subjects and in patients with ALK-positive NSCLC. The results for patients with ALK-positive NSCLC are summarised in Table 10.

Absorption.

The absolute bioavailability of alectinib was 36.9% (90% CI: 33.9%, 40.3%) under fed conditions in healthy subjects.
Alectinib reached maximal serum concentrations 4 to 6 hours post-dose when administered orally at 600 mg twice daily under fed conditions to patients with ALK-positive NSCLC. For both alectinib and M4, steady-state concentrations were reached by Day 7.
Population PK analysis estimated geometric mean accumulation ratio to be 6-fold for both alectinib and M4, and supports that alectinib exposure is dose proportional across the dose range 300 mg to 900 mg under fed conditions.
A high-fat, high-calorie meal increased the combined exposure of alectinib and M4 by 3-fold (AUC0-inf 3.1 [90% CI: 2.7, 3.6]) relative to fasted conditions following oral administration of a single 600 mg dose of alectinib.

Distribution.

Alectinib and M4 are highly bound to human plasma proteins (> 99%), independent of drug concentration. The mean in vitro human blood-to-plasma concentration ratios of alectinib and M4 are 2.64 and 2.50, respectively, at clinically relevant concentrations. The geometric mean volume of distribution at steady state (Vss) of alectinib following IV administration was 475 L, indicating extensive distribution into tissues.
Alectinib is not an in vitro substrate of efflux transporters p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1, or OATP1B3. The same is true for M4, except that M4 is a substrate of P-gp. Alectinib concentrations in the cerebrospinal fluid of patients with ALK-positive NSCLC were similar to the estimated free alectinib concentrations in their plasma.

Metabolism.

In vitro studies showed that alectinib is mainly metabolised by cytochrome p450 (CYP) isozyme CYP3A4 (40-50% of alectinib metabolism in human hepatocytes) to its major active metabolite M4. The geometric mean metabolite/parent exposure ratio at steady-state is 0.40. M4 is subsequently metabolised by CYP3A4. Results from a human mass balance study utilising 14C-labeled alectinib demonstrated that alectinib and M4 are the main circulating moieties in plasma, constituting 76% of the total radioactivity.

Excretion.

Following administration of a single oral dose of 14C-labeled alectinib to healthy subjects, the majority of radioactivity was excreted in faeces (mean recovery 97.8%, range 95.6%-100%). Most of the dose (84%) was excreted as unchanged alectinib with 6% excreted as M4. There was minimal excretion in urine (mean recovery 0.46%, range 0.30%-0.60%).
Based on a population PK analysis, the apparent clearance (CL/F) was 81.9 L/hour for alectinib and 217 L/hour for M4. The geometric mean elimination half-life was 32.5 hours for alectinib and 30.7 hours for M4 in patients with ALK-positive NSCLC.

Pharmacokinetics in special populations.

Population PK analysis of data from two phase I/II clinical trials (study 1 and study 2) was undertaken to characterise the PK of alectinib and M4 in special populations.
In the range of exposure achieved with the 600 mg twice daily dose, age, body weight, race and sex had no clinically meaningful effect on the systemic exposure of alectinib and M4. The pharmacokinetics of alectinib has not been studied in children. For hepatic and renal impairment, see Section 4.4 Special Warnings and Precautions for Use.

5.3 Preclinical Safety Data

Genotoxicity.

Alectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay but induced a slight increase in numerical aberrations in the in vitro cytogenetic assay using Chinese Hamster Lung (CHL) cells with metabolic activation, and micronuclei in a rat bone marrow micronucleus test. The mechanism of micronucleus induction was abnormal chromosome segregation (aneugenicity), and not a clastogenic effect on chromosomes.

Carcinogenicity.

Carcinogenicity studies have not been performed to establish the carcinogenic potential of Alecensa.

Juvenile development.

Juvenile animal studies have not been conducted using alectinib. In general toxicology studies, treatment of rats with doses of ≥ 27 mg/kg/day (AUC0-24h 38,200 nanogram.h/mL) alectinib resulted in changes in the growing teeth and bones. Findings in teeth included discoloration and changes in tooth size along with histopathological disarrangement of the ameloblast and odontoblast layers and degeneration/necrosis of ameloblasts. There were also decreases in the trabecular bone and increased osteoclast activity in the femur and sternum. Increased plasma alkaline phosphatase (ALP) of the bone isoform was observed at alectinib doses ≥ 6 mg/kg/day (AUC0-24h 13,900 nanogram.h/mL).

Other.

Alectinib absorbs UV light between 200 and 400 nanometre and demonstrated phototoxic potential in an in vitro photosafety test in cultured murine fibroblasts after UVA irradiation.

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsule content.

Lactose monohydrate, hyprolose, sodium lauryl sulfate, carmellose calcium, magnesium stearate.

Capsule shell.

Carrageenan, potassium chloride, titanium dioxide, carnauba wax, maize starch, hypromellose.

Printing ink.

Iron oxide red, iron oxide yellow, indigo carmine aluminium lake, carnauba wax, shellac, glyceryl monooleate.

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 Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Store in the original package to protect from light and moisture.
This medicine should not be used after the expiry date (EXP) shown on the pack.

6.5 Nature and Contents of Container

Alecensa capsules are packaged in aluminium foil blister sealed with an aluminium lidding foil containing 8 capsules per blister.
Each Alecensa multipack contains 224 (4 packs of 56) capsules.

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

1256589-74-8.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes