ZOKINVY Hard capsule Ref.[50133] Active ingredients: Lonafarnib

Treatment should be initiated by a physician experienced in the treatment of patients with progeroid syndromes or patients with rare genetic metabolic syndromes.

Posology

Starting dose

For all indications, the recommended starting dose is 115 mg/m² twice daily. The Du Bois formula was used in clinical trials and should be used to calculate body surface area for dosing. All total daily doses should be rounded to the nearest 25 mg increment and divided into two equal, or near equal, doses (see Table 1). Doses should be taken approximately 12 hours apart from one another (morning and evening).

Table 1. Recommended starting dose and administration schedule for 115 mg/m² body surface area-based dosing:

^* For patients with a body surface area of 0.30 m² to 0.38 m², the contents of a 75 mg capsule must be mixed with 10 mL of orange juice. Half of the mixture (5 mL) equates to a 37.5 mg dose of lonafarnib. This dose will be prepared and consumed twice daily (see section 6.6).

Maintenance dose

After 4 months of treatment using the starting dose of 115 mg/m² twice daily, the dose should be increased to the maintenance dose of 150 mg/m² twice daily (morning and evening). All total daily doses should be rounded to the nearest 25 mg increment and divided into two equal, or near equal, doses (see Table 2).

Table 2. Recommended maintenance dose and administration schedule for 150 mg/m² body surface area-based dosing:

Missed dose

If a dose is missed, the dose should be taken as soon as possible, up to 8 hours prior to the next scheduled dose with food. If less than 8 hours remain before the next scheduled dose, the missed dose should be skipped and the dose regimen should be resumed at the next scheduled dose.

Patients taking the starting dose of 115 mg/m² with a body surface area of 0.30 m² to 0.38 m²

Patients will need to receive a daily dose of 75 mg (37.5 mg twice daily). The contents of a lonafarnib 75 mg capsule should be mixed with 10 mL of orange juice. Only half of the 10-mL mixture will be consumed (see section 6.6).

Dose adjustment for patients with persistent vomiting and/or diarrhoea leading to dehydration or weight loss

For patients who have increased their dose to 150 mg/m² twice daily and are experiencing repeated episodes of vomiting and/or diarrhoea resulting in dehydration or weight loss (see section 4.4), the dose can be reduced to the starting dose of 115 mg/m² twice daily. All daily doses should be rounded to the nearest 25 mg increment and divided into two equal, or near equal, doses (see Table 1).

Prevention or treatment of vomiting and/or diarrhoea leading to dehydration or weight loss

Prevention or treatment of vomiting and/or diarrhoea with an anti-emetic and/or anti-diarrhoeal medicinal product can be considered (see section 4.4).

Dose adjustment for patients who cannot avoid taking a concomitant moderate CYP3A inhibitor (see section 4.5)

The patient’s daily dose of lonafarnib should be reduced by 50% and the reduced daily dose should be divided into two equal doses. Each dose should be rounded to the nearest 25 mg increment. The dosing regimen will be either 25 mg twice daily, 50 mg twice daily or 75 mg twice daily. Patients who have a reduced daily dose of 50 mg (25 mg twice daily) should mix the contents of a lonafarnib 50 mg capsule with 10 mL of orange juice to achieve the correct dose. Only half (5 mL) of the 10-mL mixture will be consumed (see section 6.6). QTc monitoring is recommended while the patient is taking a concomitant moderate CYP3A inhibitor and being treated with 50% of the indicated dose of lonafarnib. The patient should resume the body surface area indicated dose of lonafarnib 14 days after discontinuation of the moderate CYP3A inhibitor.

Dose adjustment for patients taking a concomitant weak CYP3A inhibitor and experiencing a persistent toxicity (see section 4.5)

The patient’s daily dose of lonafarnib should be reduced by 50% and the reduced daily dose should be divided into two equal doses. Each dose should be rounded to the nearest 25 mg increment. The dosing regimen will be either 25 mg twice daily, 50 mg twice daily or 75 mg twice daily. Patients who have a reduced daily dose of 50 mg (25 mg twice daily) should mix the contents of a lonafarnib 50 mg capsule with 10 mL of orange juice to achieve the correct dose. Only half (5 mL) of the 10-mL mixture will be consumed (see section 6.6). QTc monitoring is recommended while the patient is taking a concomitant weak CYP3A inhibitor and being treated with 50% of the indicated dose of lonafarnib due to the presence of a persistent toxicity. The patient should resume the body surface area indicated dose of lonafarnib 14 days after the toxicity has fully resolved or discontinuation of the weak CYP3A inhibitor.

Dose adjustment for patients with known dysfunctional polymorphisms in CYP3A4

The patient’s daily dose of lonafarnib should be reduced by 50% and the reduced daily dose should be divided into two equal doses. Each dose should be rounded to the nearest 25 mg increment. The dosing regimen will be either 25 mg twice daily, 50 mg twice daily or 75 mg twice daily. Patients who have a reduced daily dose of 50 mg (25 mg twice daily) should mix the contents of a lonafarnib 50 mg capsule with 10 mL of orange juice to achieve the correct dose. Only half (5 mL) of the 10-mL mixture will be consumed (see section 6.6). QTc monitoring is recommended.

Dose adjustment for patients requiring parenteral midazolam for a surgical procedure

Concomitant use of midazolam is contraindicated (see sections 4.3 and 4.5). Patients requiring parenteral midazolam for a surgical procedure should discontinue lonafarnib for 14 days before and 2 days after administration of midazolam.

Specific interactions with foods and drinks

Lonafarnib should not be taken with foods or juices that contain grapefruit, cranberries, pomegranates or Seville oranges (e.g., orange marmalade), otherwise known as sour or bitter oranges (see section 4.5). Taking lonafarnib with food or drinks containing these fruits or fruit juices may increase adverse reactions associated with lonafarnib.

Special populations

Patients with hepatic impairment

No dose adjustments are required in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B, respectively). Lonafarnib is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) (see sections 4.3, 4.4 and 5.2).

Patients with renal impairment

Lonafarnib has not been studied in patients with renal impairment. Because lonafarnib and metabolite HM21 are only excreted to a limited extent via urine, no dose adjustments are required in patients with renal impairment (see sections 4.4 and 5.2).

Paediatric population

The posology is the same in adults and children 12 months of age and older.

The safety and efficacy of lonafarnib in children less than 12 months of age have not been established. No data are available (see section 5.1).

Method of administration

Lonafarnib is intended for oral use. The capsule should be swallowed whole. The capsule should not be chewed. Each dose is to be taken with food.

For patients unable to swallow the capsule whole, instructions on mixing the capsule contents with orange juice are provided in section 6.6.

In the event of acute overdose, supportive medical care should be given as clinically indicated, including fluid replacement to avoid electrolyte imbalance and close monitoring of vital signs. There is no antidote to lonafarnib to reverse overdose.

3 years.

Store in the original package. Keep the bottle tightly closed in order to protect from moisture. This medicinal product does not require any special temperature storage conditions.

HDPE bottle, containing desiccant in a cannister and capsules, with induction seal and polypropylene cap. Pack size of 30 hard capsules.

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

Patients unable to swallow capsules whole

If capsules cannot be swallowed whole, capsules can be opened and the contents of the capsule can be mixed with orange juice.

Step 1: Using a clean medicine cup, measure either 5 mL or 10 mL of orange juice. You can choose to use 5 mL or 10 mL of orange juice.

Step 2: Pour the orange juice measured in Step 1 into a clean cup.

Step 3: Hold a capsule above the cup containing the orange juice. Hold the capsule between your thumb and forefinger on both sides. Gently twist and pull apart the capsule.

Step 4: Empty the contents of the capsule directly into the cup containing the orange juice.

Step 5: Using a clean spoon, mix the capsule contents and orange juice well. If only 1 capsule is to be taken, skip to Step 7. If 2 capsules are to be taken proceed to Step 6.

Step 6: If 2 capsules will be taken, repeat Steps 1 through 5 for the second capsule. After finishing, go to Steps 7, 8 and 9.

Step 7: Take all of the mixture with food within about 10 minutes of preparing. Each dose must be mixed and consumed within 10 minutes. The mixture should only be prepared at the time it is to be consumed.

Step 8: Rinse the medicine cup used to measure the orange juice and fill it with 5 mL of water for each capsule mixed with orange juice.

Step 9: Pour the water measured in Step 8 into the cup used to mix the Zokinvy and orange juice. Gently swirl the water around the cup. Consume the water.

Patients with a body surface area between 0.30 m² and 0.38 m², patients taking Zokinvy and a weak CYP3A inhibitor and experiencing persistent toxicities or patients with a dysfunctional CYP3A4 polymorphism requiring a reduced daily dose of less than or equal to 50 mg

Patients with a body surface area between 0.30 m² and 0.38 m² require a daily dose of 75 mg (37.5 mg twice daily). Some patients taking Zokinvy concomitantly with a weak CYP3A inhibitor and experiencing persistent side-effects or patients with a dysfunctional CYP3A4 polymorphism may require a daily dose of 50 mg (25 mg twice daily). In these instances, a Zokinvy 75 mg or 50 mg capsule will need to be mixed with 10 mL of orange juice to reach the appropriate dose. Only half of the 10-mL mixture will be consumed yielding a dose of either 25 mg or 37.5 mg.

Step 1: Use a clean medicine cup and fill it with 10 mL of orange juice.

Step 2: Pour the orange juice measured in Step 1 into a clean cup for mixing.

Step 3: Depending on your doctor’s direction, hold either a Zokinvy 75 mg or 50 mg capsule above the cup containing the orange juice. Hold the capsule between your thumb and forefinger on both sides. Gently twist and pull apart the capsule.

Step 4: Empty the contents of the capsule directly into the cup containing the orange juice.

Step 5: Using a clean spoon, mix the capsule contents and orange juice well.

Step 6: Pour 5 mL of the orange juice and mixture from the mixing cup into a clean medicine cup.

Step 7: Take the 5-mLmixture with food and within about 10 minutes of preparing. Each dose must be mixed and consumed within 10 minutes. The mixture should only be prepared at the time it is to be consumed.

Step 8: Fill the medicine cup used to consume the mixture with 5 mL of water.

Step 9: Gently swirl the water around the medicine cup. Consume the water.