Lonafarnib

Concomitant use of moderate and strong CYP3A inducers may reduce the efficacy of lonafarnib and they should be avoided.

Moderate CYP3A inducers

No interaction studies have been conducted with a moderate CYP3A inducer. There is no efficacy data available demonstrating that lonafarnib remains effective when given concomitantly with a moderate CYP3A inducer. Therefore, the concomitant use of lonafarnib and a moderate CYP3A inducer should be avoided, and therapeutic alternatives sought.

Strong CYP3A inducers

Co-administration of a single oral dose of 50 mg lonafarnib (combined with a single oral dose of 100 mg ritonavir) following 600 mg rifampin once daily for 8 daysresulted in the C_max of lonafarnib being reduced by 92% and the AUC being reduced by 98%, when compared to rifampin alone in healthy adult subjects. There is no efficacy data available that demonstrates lonafarnib remains effective when administered concomitantly with a strong CYP3A inducer. Therefore, the concomitant use of lonafarnib and a strong CYP3A inducer should be avoided, and therapeutic alternatives sought.

Concomitant use of weak CYP3A inducers may reduce the efficacy of lonafarnib and should be avoided.

No interaction studies have been conducted with a weak CYP3A inducer. There is no efficacy data available demonstrating that lonafarnib remains effective when given concomitantly with a weak CYP3A inducer. Therefore, the concomitant use of lonafarnib and a weak CYP3A inducer should be avoided, and therapeutic alternatives sought. If co-administration with a weak CYP3A inducer is unavoidable, maintain the current dose of lonafarnib. If the patient has not already been escalated to the maintenance dose of 150 mg/m² twice daily, the timing of their scheduled dose increase should be maintained.

When lonafarnib was co-administered with the CYP2C19 substrate omeprazole in healthy adult subjects, multiple dose lonafarnib (75 mg twice daily for 5 consecutive days) increased omeprazole (single 40 mg oral dose) C_max by 28% and AUC by 60%. Patients taking medicinal products that are CYP2C19 substrates should be monitored during this period for potential adverse reactions, with dose adjustments made as necessary.

When lonafarnib was co-administered with the P-glycoprotein substrate fexofenadine in healthy adult subjects, multiple dose lonafarnib (100 mg twice daily for 5 consecutive days) increased fexofenadine (single 180 mg oral dose) C_max by 21% and AUC by 24%. When lonafarnib is co-administered with P-glycoprotein substrates (e.g., digoxin, dabigatran) where minimal concentration changes may lead to serious or life-threatening toxicities, monitor for adverse reactions and reduce the dose of the P-glycoprotein substrate in accordance with its approved product labelling.

No interaction studies have been conducted with a moderate CYP3A inhibitor. Concomitant use of lonafarnib and a moderate CYP3A inhibitor should be avoided.

Dose adjustment for patients who cannot avoid taking a concomitant moderate CYP3A inhibitor

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. 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.

No interaction studies have been conducted with a weak CYP3A inhibitor. No dose adjustment is considered necessary; however, if the concomitant use of a weak CYP3A inhibitor induces a persistent toxicity, the dose of lonafarnib should be reduced by 50% and QTc monitoring is recommended.

Dose adjustment for patients taking a concomitant weak CYP3A inhibitor and experiencing a persistent toxicity

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. 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.

When lonafarnib was co-administered with loperamide in healthy adult subjects, multiple dose lonafarnib (100 mg twice daily for 5 consecutive days) increased loperamide (single 2 mg oral dose) C_max by 214% and AUC by 299%. The dose of loperamide should not exceed 1 mg daily. In the event more than 1 mg of loperamide daily is to be administered, the dose should be slowly increased with caution as needed to treat diarrhoea.

Based on in vitro data, lonafarnib is a MATE1/MATE2-K inhibitor at clinically relevant maximal systemic concentrations and could potentially precipitate a clinically relevant interaction. Currently, the only identified clinically relevant substrate of MATE1/MATE2-K is metformin. Concomitant use of metformin and lonafarnib should be avoided. If metformin is required, clinicians should carefully monitor the patient for interactions with lonafarnib.

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. QTc monitoring is recommended.

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.

There are no or limited data from the use of lonafarnib in pregnant women. Studies in animals have shown reproductive toxicity. Lonafarnib is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether lonafarnib is excreted in human milk. Animal studies have shown excretion of lonafarnib in milk. A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue therapy with lonafarnib taking into account the benefit of breast-feeding to the child and the benefit of therapy to the woman.

Women of childbearing potential/Contraception in males and females

Females of childbearing potential must use effective contraception during treatment with lonafarnib and for at least 1 week after the final dose. Males with female partners of reproductive potential must use effective contraception during treatment with lonafarnib and for at least 3 months after the final dose.

Effects of lonafarnib on contraceptive steroids have not been studied. A barrier method must be added if systemic steroids are used for contraception.

Fertility

There are no data on the effects of lonafarnib on fertility in humans. In animal studies, lonafarnib resulted in changes in the male and female reproductive tracts and resorptions. The potential effect of lonafarnib on fertility in humans is currently unknown.

Lonafarnib has a minor influence on the ability to drive and use machines. Fatigue may occur following the administration of lonafarnib.

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.

The most serious adverse reactions are increased alanine aminotransferase (3.6%), increased aspartate aminotransferase (3.6%), cerebral ischaemia (3.2%), pyrexia (1.6%) and dehydration (1.6%).

Tabulated list of adverse reactions

Adverse reactions occurring in the clinical trials are presented in the table below 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.

^a Abdominal pain includes abdominal pain and abdominal pain upper

Description of selected adverse reactions

Gastrointestinal adverse reactions

Gastrointestinal adverse reactions (vomiting [85.7%], diarrhoea [77.8%], nausea [38.1%]) were the most frequently reported adverse reactions. Of the patients with treatment related vomiting, 29 (53.7%) patients had Grade 1 vomiting (defined as no intervention required) and 25 (46.3%) had Grade 2 vomiting (defined as outpatient intravenous hydration; medical intervention required). Of these patients with treatment related nausea, 23 (95.8%) had Grade 1 nausea (defined as loss of appetite without alteration in eating habits) and 1 (4.2%) patient had Grade 2 nausea (defined as oral intake decreased without significant weight loss, dehydration or malnutrition). During the first 4 months of treatment in ProLon1, 19 (67.9%) patients had vomiting and 10 (35.7%) patients had nausea. By the end of therapy, 4 (14.3%) patients required anti-emetics or anti-nauseants. A total of 4 patients discontinued treatment, mostly due to nausea or vomiting.

Most patients with treatment related diarrhoea (approximately 94%) experienced mild or moderate diarrhoea; 38 (77.6%) patients reported Grade 1 (defined as an increase of less than 4 stools per day over baseline) and 8 (16.3%) 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). Three (6.1%) 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). During the first 4 months of treatment in ProLon1, 23 (82.1%) patients had diarrhoea; by the end of therapy, 3 (10.7%) patients had diarrhoea. Twelve (42.9%) patients were treated with loperamide.

Electrolyte abnormalities

Electrolyte abnormalities (hypermagnesaemia, hypokalaemia, hyponatraemia) were experienced by 4 (6.3%) patients. Of the 2 patients who experienced hypermagnesaemia, 2 (100%) patients had Grade 1 hypermagnesaemia (defined as > upper limit of normal [ULN] to 3.0 mg/dL; >ULN to 1.23 mmol/L). Of the 2 patients who experienced hypokalaemia, 1 (50%) patient had Grade 1 hypokalaemia (defined as < lower limit of normal [LLN] to 3.0 mmol/L) and 1 (50%) patient had Grade 3 hypokalaemia (defined as <3.0 to 2.5 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). Dehydration was experienced by 3 (4.8%) patients. Of the 3 patients who experienced dehydration, 1 (33.3%) patient had Grade 1 dehydration (defined as increased oral fluids indicated; dry mucous membranes; diminished skin turgor) and 2 (66.7%) patients had Grade 2 dehydration (defined as intravenous fluids indicated).

Aminotransferase increases

Increased alanine aminotransferase was recorded for 14 (50.0% of patients) ProLon1 patients. Of the patients with increased alanine aminotransferase, 11 (78.6%) patients experienced a Grade 1 increase (defined as greater than ULN to 3.0 times ULN if baseline was normal; 1.5 to 3.0 times baseline if baseline was abnormal), 1 (7.1%) patient experienced a Grade 2 increase (defined as >3.0 to 5.0 times ULN if baseline was normal; >3.0 to 5.0 x baseline if baseline was abnormal), and 2 (14.3%) patients experienced a Grade 3 increase (defined as >5.0 to 20.0 x ULN if baseline was normal; >5.0 to 20.0 x baseline if baseline was abnormal).

Increased aspartate aminotransferase was recorded for 18 (64.3%) ProLon1 patients. Of these patients, 17 (94.4%) patients experienced a Grade 1 increase (defined as greater than ULN to 3.0 times ULN if baseline was normal; 1.5 to 3.0 times baseline if baseline was abnormal) and 1 (5.6%) patient experienced a Grade 3 increase (defined as >5.0 to 20.0 x ULN if baseline was normal; >5.0 to 20.0 x baseline if baseline was abnormal).