ZOKINVY

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). 38 m2, the contents of a 75 mg capsule must be mixed with 10 mL of orange juice. 5 mg dose of lonafarnib. 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). 96 – 1 300 2 2 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. 5 mg twice daily). The contents of a lonafarnib 75 mg capsule should be mixed with 10 mL of orange juice.

6). 4), the dose may 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). 4). 5) When adding lonafarnib to an existing treatment regimen containing a moderate CYP3A inhibitor, a lower starting dose of lonafarnib might be reasonable.

If the concomitantly taken moderate CYP3A inhibitor will be discontinued, the lonafarnib dose may be increased (body surface area-based dosing). 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.

6). QTc monitoring is recommended. 5). Patients requiring parenteral midazolam for a surgical procedure should discontinue lonafarnib for 14 days before and 2 days after administration of midazolam. 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). 2). Patients with renal impairment Lonafarnib has not been studied in patients with renal impairment.

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 […]

Summary of the safety profile The most frequently occurring adverse reactions are: vomiting (86%), diarrhoea (78%), increased aspartate aminotransferase (64%), increased alanine aminotransferase (50%), decreased appetite (41%), nausea (38%), abdominal pain (35%), fatigue (29%), decreased weight (27%), constipation (18%) and upper respiratory tract infection (11%).

Most adverse reactions occurred within the first 4 weeks following initiation of treatment and in general steadily decreased with increasing duration of treatment. 6%). Tabulated list of adverse reactions Adverse reactions occurring in the clinical trials are presented in Table 3 by System Organ Class and Preferred Term.

Frequencies are defined as: 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) or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing frequency within each System Organ Class.

1%]) were the most frequently reported adverse reactions. 3%) had Grade 2 vomiting (defined as outpatient intravenous hydration; medical intervention required). 2%) patient had Grade 2 nausea (defined as oral intake decreased without significant weight loss, dehydration or malnutrition).

7%) patients had nausea. 4). A total of 4 patients discontinued treatment, mostly due to nausea or vomiting. 3%) patients reported Grade 2 treatment related diarrhoea (defined as an increase of 4 to 6 stools per day over baseline; limiting instrumental activities of daily living).

1%) patients reported Grade 3 diarrhoea (defined as an increase of 7 or more stools per day over baseline; hospitalisation indicated; severe increase in ostomy output compared to baseline; limiting self-care activities of daily living).

7%) patients had diarrhoea. 9%) patients were treated with loperamide. 3%) patients. 23 mmol/L). 5 mmol/L; hospitalisation indicated). Of the 1 patient that experienced hyponatraemia, 1 (100%) patient had Grade 1 hyponatraemia (defined as <LLN to 130 mmol/L).

8%) patients. 7%) patients had Grade 2 dehydration (defined as intravenous fluids indicated). 0% of patients) ProLon1 patients. 0 x baseline if baseline […]

4 Special warnings and precautions for use Age at start of treatment Treatment with lonafarnib should be initiated as soon as a diagnosis has been made. 1). , vomiting, nausea and diarrhoea) in the first few months of treatment. 8). The severity of gastrointestinal adverse reactions, especially during the first 4 months of treatment, should be closely monitored.

When gastrointestinal adverse reactions occur, monitoring the patient’s weight, caloric consumption and fluid volume intake should be done on a regular basis. In some cases, persistent diarrhoea can result in hypovolaemia, which should be treated by infusion or orally.

5). 5) due to an increased risk of extreme sedation and respiratory depression. For patients requiring midazolam as a component of anaesthesia for a surgical procedure, lonafarnib treatment should be discontinued for 14 days before and 2 days after parenteral midazolam is administered.

8). Signs and symptoms of reduced liver function should be assessed on a consistent basis. Liver function should be measured annually or at the onset of any new or worsening signs or symptoms of liver dysfunction. 3). Signs and symptoms of reduced renal function should be assessed on a consistent basis.

Renal function should be measured annually or at the onset of any new or worsening signs or symptoms associated with renal dysfunction. 3). An ophthalmological evaluation should be performed annually and at the onset of any new visual disturbances during therapy.

5). 5). Concomitant use of weak CYP3A inducers Concomitant use of weak CYP3A inducers may reduce the efficacy of lonafarnib and should be avoided. 5). Subjects with known dysfunctional polymorphisms in CYP3A4 Subjects with a known dysfunctional polymorphism in CYP3A4 should start therapy at 50% of the indicated dose.

5). Other progeroid syndromes Lonafarnib is not expected to be effective for the treatment of progeroid syndromes caused by mutations in genes other than LMNA or ZMPSTE24 and laminopathies not associated with the accumulation of progerin-like proteins.

Lonafarnib is not expected to be effective in the treatment of the following progeroid syndromes: Werner syndrome, Bloom syndrome, Rothmund–Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy and ataxia-telangiectasia.

Excipients with known effect Zokinvy contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

1. 5). 5). 2).