Zokinvy

Package leaflet: Information for the patient

Zokinvy 50 mg hard capsules, 75 mg hard capsules

lonafarnib

This medicinal product is under additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read all of this leaflet carefully before you start taking this medicine, because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful to them.
• If you experience any side effect, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

1. What Zokinvy is and what it is used for
2. What you need to know before taking Zokinvy
3. How to take Zokinvy
4. Possible side effects
5. How to store Zokinvy
6. Contents of the pack and other information

1. What Zokinvy is and what it is used for

What Zokinvy is
Zokinvy contains the active substance lonafarnib.
What Zokinvy is used for
This medicine is used to treat patients aged 12 months and older who have the following rare diseases:

• Hutchinson-Gilford progeria syndrome
• Processing-deficient progeroid laminopathies

These diseases are caused by genetic mutations affecting genes needed to produce certain proteins. Normal versions of these proteins help keep cells strong and stable. However, the mutated genes lead to an accumulation of harmful forms of proteins called progerin or progerin-like proteins. These harmful proteins cause cellular damage similar to the effects of aging.
How Zokinvy works
Zokinvy works by helping to reduce the buildup of harmful progerin or progerin-like proteins.

2. What you need to know before taking Zokinvy

Do not take Zokinvy

• if you are allergic to lonafarnib or to any of the other ingredients of this medicine (listed in section 6);
• with medicines known as strong CYP3A inhibitors (these can reduce the breakdown of Zokinvy in the body, leading to a greater number of side effects; see Other medicines and Zokinvy, below);
• with the medicine midazolam;
• with the medicines atorvastatin, lovastatin, simvastatin;
• if you have severe liver impairment.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before taking Zokinvy.
Inform your doctor immediately if:

• you are over 10 years of age. Treatment outcomes may vary depending on age at the start of Zokinvy treatment;
• you experience persistent vomiting or diarrhoea, or prolonged loss of appetite or weight (see section 4);
• you start taking the anti-diarrhoeal medicine loperamide. Due to the interaction between Zokinvy and loperamide, it is important that your doctor provides guidance on dosing and monitors the use of this medicine;
• you are scheduled for surgery. You must not use midazolam, a medicine commonly used during surgical procedures, with Zokinvy. Your doctor can provide instructions for this situation;
• you have increased liver enzyme levels shown by blood tests. Your doctor must monitor liver function during treatment with this medicine;
• you develop any symptoms of kidney problems. Your doctor must monitor kidney function during treatment with this medicine;
• you notice any new changes in vision. Your doctor must monitor your vision and eye health during treatment with this medicine;
• you are taking a medicine that is a moderate or strong CYP3A inducer. These types of medicines should be avoided (see Other medicines and Zokinvy, below);
• you are taking a medicine that is a moderate CYP3A inhibitor. These types of medicines should be avoided (see Other medicines and Zokinvy, below);
• you have a known dysfunctional polymorphism in CYP3A4;
• you have a progeroid syndrome caused by a mutation in a gene other than LMNA or ZMPSTE24 that does not cause accumulation of harmful proteins called progerin or progerin-like proteins. Zokinvy is not expected to be effective in these types of progeroid syndromes. Examples of progeroid syndromes for which Zokinvy is not expected to provide benefit include Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, and ataxia-telangiectasia.

Children
Do not give this medicine to children under 12 months of age, as it has not been studied in this age group.
Other medicines and Zokinvy
Tell your doctor or pharmacist if you are taking or might take any other medicines.
Some medicines may interact with Zokinvy if taken together. The following medicines must not be taken in combination with Zokinvy:

• medicines that are strong CYP3A inhibitors (these can reduce the breakdown of Zokinvy in the body, leading to a greater number of side effects; consult your pharmacist or doctor if any of the other medicines you are taking belong to this category);
• medicines that are weak or moderate CYP3A inhibitors (these can reduce the breakdown of Zokinvy in the body, leading to a greater number of side effects; consult your pharmacist or doctor if any of the other medicines you are taking belong to this category). Your doctor may temporarily reduce the dose of Zokinvy while you are taking a weak or moderate CYP3A inhibitor;
• midazolam (used to treat epileptic seizures and for surgical procedures; inform your doctor that you are taking Zokinvy if you are scheduled for surgery);
• atorvastatin, lovastatin, or simvastatin (used to lower cholesterol in the blood);
• medicines that are strong, moderate, or weak CYP3A inducers (these can increase the breakdown of Zokinvy in the body, making the medicine less effective; consult your pharmacist or doctor if any of the other medicines you are taking belong to this category);
• loperamide (used to treat diarrhoea). The dose of loperamide must not exceed 1 mg per day. Children under 2 years of age must not take loperamide;
• metformin (used to treat type 2 diabetes);
• medicines that are substrates of CYP2C19 (consult your pharmacist or doctor if any of the other medicines you are taking belong to this category). If you need to take a CYP2C19 substrate, your doctor may need to adjust the dose of the CYP2C19 substrate and monitor side effects more closely;
• St. John’s wort or products containing St. John’s wort (a herbal medicine used to treat mild depression);
• medicines that are substrates of P-glycoprotein (consult your pharmacist or doctor if any of the other medicines you are taking belong to this category). If you need to take a P-glycoprotein substrate, your doctor may need to adjust the dose of the P-glycoprotein substrate and monitor side effects more closely;
• medicines that are substrates of OCT1 (consult your pharmacist or doctor if any of the other medicines you are taking belong to this category);
• oral contraceptives.

Zokinvy with food and drink
Do not take Zokinvy with food or drinks containing grapefruit, cranberry, pomegranate, or bitter orange (such as marmalade made from bitter oranges). Food or drinks containing these fruits may increase the side effects of Zokinvy.
Pregnancy, breast-feeding, and fertility
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breast-feeding, ask your doctor or pharmacist for advice before taking this medicine.
Zokinvy has not been studied in pregnant women.
Zokinvy is not recommended during pregnancy.
Women of childbearing potential must use effective contraception during treatment with Zokinvy and for at least 1 week after the last dose. Men with female partners of childbearing potential must use effective contraception during treatment with Zokinvy and for at least 3 months after the last dose. Add a barrier contraceptive method if systemic steroids are used for contraception.
It is not known whether Zokinvy passes into breast milk or whether it may affect a breastfed child. If you wish to breast-feed, discuss with your doctor first the benefits and possible risks of breast-feeding or of interrupting treatment with Zokinvy.
It is not yet known whether this medicine affects fertility in men or women.
Driving and using machines
Zokinvy has a minor influence on the ability to drive and use machines. Fatigue may occur after administration of Zokinvy.
Zokinvy contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. is essentially “sodium-free”.

3. How to take Zokinvy

Take this medicine exactly as instructed by your doctor or pharmacist. If you have any doubts, consult your doctor or pharmacist.

• Zokinvy should be taken as 1 or 2 capsules twice daily, approximately 12 hours apart (morning and evening), with food. The dose of Zokinvy depends on your height and weight.
• Your doctor will determine the appropriate starting dose of Zokinvy for you. This may involve taking capsules of different strengths to achieve the correct amount. After 4 months of treatment with Zokinvy, your doctor may increase the dose.
• You must know how many capsules to take at each dose and the strength of each capsule you need. Ask your doctor, pharmacist, or nurse to write down these instructions for you (including the color of the capsule(s) to take for each dose).
• Take the capsules with food and with enough water to swallow them. Taking Zokinvy with food may help reduce side effects.

If you are unable to swallow a whole Zokinvy capsule

• If you cannot swallow a whole Zokinvy capsule, follow these instructions to mix the capsule contents with orange juice.

What you need to mix Zokinvy with orange juice

• Prepare the mixture with Zokinvy immediately each time you need to take it.
• Select the correct number of Zokinvy capsules according to your prescribed dose. Place the capsule(s) on a clean, flat surface.
• Use only orange juice. Do not use other beverages to mix with Zokinvy.
• A clean, graduated medicine cup with markings at 5 mL and 10 mL.
• One clean glass for each Zokinvy capsule to be mixed.
• A clean spoon for stirring the mixture.

or
How to mix Zokinvy with orange juice
Step 1:

measure 5 mL or 10 mL of orange juice using
a clean, graduated medicine cup;
you may use either 5 mL or 10 mL of orange juice.
Step 2:

pour the measured orange juice from
step 1 into a clean glass.
Step 3:

hold one Zokinvy capsule above the glass
containing the orange juice;
hold the capsule on both sides between your
thumb and index finger;
gently twist and open the capsule.
Step 4:

empty the entire contents of the capsule into the
glass containing the orange juice.
Step 5:

thoroughly mix the capsule contents and orange
juice using a clean spoon;
if you are taking only 1 capsule, proceed to
step 7;
if you are taking 2 capsules, proceed to step 6.
Step 6:
if you are taking 2 capsules, repeat steps 1 to 5
for the second capsule;
once the second capsule is mixed, the two
portions may be combined into a single glass or
left in 2 separate glasses;
then proceed to steps 7, 8, and 9.
Step 7: TAKE IT WITHIN

take the entire Zokinvy mixture:
10 minutes
with food;
within approximately 10 minutes of preparation.
Each dose must be mixed and taken within 10 minutes.
The mixture should only be prepared at the time of dosing.
Step 8:

rinse the medicine cup used to measure the
orange juice and refill it with 5 mL of water for
each capsule mixed with orange juice.
Step 9:

pour the measured water from step 8 into the
(a) glass used to mix Zokinvy and orange juice;
gently stir the water in the glass (b).
Drink the water.

(b)
Patients starting Zokinvy therapy with a body surface area between 0.30 m² and 0.38 m²,
patients taking a weak CYP3A inhibitor with Zokinvy and experiencing persistent toxicity,
and patients with a dysfunctional CYP3A4 polymorphism requiring a daily dose of 50 mg or less
Before starting to mix Zokinvy with orange juice, read "What you need to mix Zokinvy with orange juice".
For patients with a body surface area between 0.30 m² and 0.38 m², the initial daily dose of Zokinvy is 75 mg (37.5 mg twice daily with food). Each dose should be prepared immediately using one 75 mg capsule mixed with 10 mL of orange juice. Half of the 10 mL mixture will be taken.
For patients taking Zokinvy with a weak CYP3A inhibitor who experience persistent side effects or who have a dysfunctional CYP3A4 polymorphism, the doctor may reduce the daily dose of Zokinvy by 50%. Prepare each dose immediately. If the reduced daily dose is 50 mg (25 mg twice daily), mix the contents of one 50 mg capsule with 10 mL of orange juice. Half of the 10 mL mixture will be taken. Generally, 14 days after stopping treatment with the weak CYP3A inhibitor or after resolution of side effects, the doctor will increase the dose back to the previous level. Your doctor will provide specific instructions.
Step 1:

pour 10 mL of orange juice into a clean, graduated medicine cup.
Step 2:

pour the orange juice measured in step 1 into a

clean mixing glass.
Step 3:

depending on your doctor’s instructions, place one
Zokinvy capsule (75 mg or 50 mg) above the glass
containing the orange juice;
hold the capsule on both sides between your thumb
and index finger;
gently twist and open the capsule.
Step 4:

empty the entire contents of the capsule into the
glass containing the orange juice.
Step 5:

thoroughly mix the capsule contents and orange
juice using a clean spoon.
Step 6:

pour 5 mL of the orange juice and Zokinvy mixture
from the mixing glass into a clean, graduated
medicine cup.
Fill
up to
5 mL
Step 7: TAKE IT WITHIN

take the 5 mL mixture of Zokinvy and orange juice
from the medicine cup: 10 minutes
with food;
within approximately 10 minutes of preparation.
Each dose must be mixed and taken within 10 minutes.
The mixture should only be prepared at the time of dosing.
Step 8:

pour 5 mL of water into the medicine cup used to
take the Zokinvy and orange juice mixture.
Step 9:
gently stir the water in the medicine cup.

Drink the water.
Drink plenty of water while taking Zokinvy
It is important to drink plenty of water and other fluids while taking Zokinvy. This may help reduce problems related to diarrhea or vomiting.
Ask your doctor how much water or other fluids you should drink each day.
Your doctor will advise you on which fluids you can drink to ensure you are getting the right amount of fluids daily.
Do not consume foods or juices containing grapefruit, cranberry, pomegranate, or Seville (bitter) orange.
If you take more Zokinvy than you should
If you take more capsules than prescribed, stop taking the medicine and contact your doctor immediately.
If you forget to take Zokinvy
If you forget to take a dose and there are at least 8 hours until your next scheduled dose, take the missed dose as soon as possible with food. If there are less than 8 hours until your next scheduled dose, do not take the missed dose; resume your regular dosing schedule with the next dose.
If you stop taking Zokinvy
Do not stop treatment with Zokinvy without consulting your doctor.
If you have any questions about using this medicine, speak to your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
Serious side effects. Contact your doctor immediately if:

• you have persistent nausea, vomiting or diarrhoea causing loss of appetite, weight loss or dehydration. Vomiting or diarrhoea are very common (may affect more than 1 in 10 people) and may lead to electrolyte imbalances requiring supportive treatment. Your doctor may monitor your weight, appetite, and the amount of food and fluids you consume to help identify any of these potential electrolyte imbalances.

Contact your doctor immediately if you notice any of the serious side effects listed above.
Very common (may affect more than 1 in 10 people):

• increased liver enzymes in blood tests (indicating liver stress)
• stomach ache
• fatigue
• constipation
• sinus infections or other upper respiratory tract infections
• decreased haemoglobin in blood tests
• decreased bicarbonate in blood tests

Common (may affect up to 1 in 10 people):

• body aches and pain, including back pain and limb pain
• fever
• decreased levels of sodium, potassium, albumin, creatinine in blood tests
• increased levels of magnesium in blood tests
• cough
• flatulence
• skin rash
• itching
• cerebral ischaemia (stroke)
• headache
• runny nose
• nasal congestion (stuffy nose)
• nosebleeds
• sore throat
• depression
• oral pustules (mouth sores)
• painful swollen blister-like lesion near the anus (perianal abscess)
• lung infection
• influenza
• decreased number of blood cells (such as white blood cells) in blood tests
• tingling in hands and feet
• dizziness
• irritation, inflammation or ulcers of the large intestine (colitis)
• indigestion (may include bloating, discomfort, feeling excessively full or gas)
• inflammation of the stomach lining (gastritis)
• bleeding from the large intestine, rectum or anus
• dry skin
• darkening of the skin (hyperpigmentation)
• chest pain
• chills
• dental fracture

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Zokinvy

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and on the bottle after "Exp.".
The expiry date refers to the last day of that month.
Store in the original packaging. Keep the bottle tightly closed to protect the medicine from moisture.
This medicine does not require special storage conditions regarding temperature.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of
medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Zokinvy contains

• The active substance is lonafarnib. Zokinvy 50 mg hard capsules: each capsule contains 50 mg of lonafarnib. Zokinvy 75 mg hard capsules: each capsule contains 75 mg of lonafarnib.
• The other components are as follows:
  Capsule contents: sodium croscarmellose (see section 2 “Zokinvy contains sodium”), magnesium stearate, poloxamer, povidone and anhydrous colloidal silica
  Capsule shell:
  Zokinvy 50 mg hard capsules: gelatin, titanium dioxide, yellow iron oxide and sunflower lecithin
  Zokinvy 75 mg hard capsules: gelatin, titanium dioxide, yellow iron oxide, red iron oxide and sunflower lecithin
  Printing ink: shellac, black iron oxide

Description of the appearance of Zokinvy and package contents
Zokinvy 50 mg hard capsules are opaque yellow hard capsules marked with “LNF” and “50” in black ink.
Zokinvy 75 mg hard capsules are opaque light orange hard capsules marked with “LNF” and “75” in black ink.
The bottle pack contains 30 hard capsules and a desiccant. The desiccant is located inside a container placed within the bottle containing the capsules.

Marketing Authorization Holder
TMC Pharma (EU) Limited,
G24A ArcLabs Research & Innovation Centre,
Carriganore,
Waterford,
X91 P20H
Ireland

Manufacturer
ABF Pharmaceutical Services GmbH
Brunner Straße 63/18-19
A-1230 Vienna
Austria
Sciensus International B.V.
Bijsterhuizen 3142
6604 LV, Wijchen
The Netherlands

This medicinal product has been granted a marketing authorization under “exceptional circumstances”.
This means that, due to the rarity of the disease, it has not been possible to obtain complete information about this medicinal product.
The European Medicines Agency will review annually any new information regarding this medicinal product, and this package leaflet will be updated if necessary.

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu. In addition, links to other websites on rare diseases and related therapeutic treatments are provided.
This leaflet is available in all languages of the European Union/European Economic Area on the website of the European Medicines Agency.