Active Ingredient: Lonafarnib
Lonafarnib is indicated for the treatment of patients 12 months of age and older with a genetically confirmed diagnosis of Hutchinson-Gilford progeria syndrome or a processing-deficient progeroid laminopathy associated with either a heterozygous LMNA mutation with progerin-like protein accumulation or a homozygous or compound heterozygous ZMPSTE24 mutation.
For this indication, competent medicine agencies globally authorize below treatments:
For:
Oral, 115 milligrams lonafarnib per square meter of body surface, once every 12 hours, over the duration of 4 months. Afterwards, oral, 150 milligrams lonafarnib per square meter of body surface, once every 12 hours.
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:
| Body surface area (m²) | Total daily dose rounded to nearest 25 mg |
|---|---|
| 0.30 – 0.38 | 75 |
| 0.39 – 0.48 | 100 |
| 0.49 – 0.59 | 125 |
| 0.6 – 0.7 | 150 |
| 0.71 – 0.81 | 175 |
| 0.82 – 0.92 | 200 |
| 0.93 – 1 | 225 |
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:
| Body surface area (m²) | Total daily dose rounded to nearest 25 mg | ||
|---|---|---|---|
| 0.30 – 0.37 | 100 | ||
| 0.38 – 0.45 | 125 | ||
| 0.46 – 0.54 | 150 | ||
| 0.55 – 0.62 | 175 | ||
| 0.63 – 0.7 | 200 | ||
| 0.71 – 0.79 | 225 | ||
| 0.8 – 0.87 | 250 | 0.88 – 0.95 | 275 |
| 0.96 – 1 | 300 |
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 will need to receive a daily dose of 75 mg (37.5 mg twice daily).
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, 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).
Prevention or treatment of vomiting and/or diarrhoea with an anti-emetic and/or anti-diarrhoeal medicinal product can be considered.
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).
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. QTc monitoring is recommended.
Concomitant use of midazolam is contraindicated. Patients requiring parenteral midazolam for a surgical procedure should discontinue lonafarnib for 14 days before and 2 days after administration of midazolam.
Electrocardiograms (ECGs) should be obtained prior to initiating lonafarnib and monitored during lonafarnib treatment. For patients with QTc intervals ≥500 ms, lonafarnib treatment should be withheld until normal QTc intervals are observed upon repeated ECG monitoring. Then lonafarnib should be resumed at the same dose. If QTc intervals ≥500 ms are observed upon repeated ECG monitoring in patients, lonafarnib treatment discontinuation should be considered.
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. Taking lonafarnib with food or drinks containing these fruits or fruit juices may increase adverse reactions associated with lonafarnib.
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