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

Age at start of treatment

Treatment with lonafarnib should be initiated as soon as a diagnosis has been made. The clinical data indicate that the expected survival benefit of lonafarnib treatment in Hutchinson-Gilford progeria syndrome (HGPS) patients who started treatment at 10 years of age or above is less compared to those who started at a younger age (see section 5.1).

Treatment initiation with lonafarnib in older patients should be balanced against the side effects (i.e., vomiting, nausea and diarrhoea) in the first few months of treatment.

Gastrointestinal adverse reactions and dehydration

Electrolyte abnormalities (hypermagnesaemia, hypokalaemia, hyponatraemia) have been reported (see section 4.8). 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.

Patients experiencing diarrhoea and treated with the anti-diarrhoeal loperamide should be monitored for adverse reactions associated with increased exposure to loperamide (see section 4.5).

Patients requiring parenteral midazolam for a surgical procedure

Concomitant administration of lonafarnib and midazolam is contraindicated (see sections 4.3 and 4.5) 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.

Abnormal liver function

Increased liver enzymes, such as aspartate aminotransferase or alanine aminotransferase, have been reported (see section 4.8). 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.

Nephrotoxicity

Lonafarnib caused nephrotoxicity in rats with clinical chemistry and urinalysis changes, at plasma exposures approximately equal to the human dose (see section 5.3). 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.

Retinal toxicity

Lonafarnib caused rod-dependent, low-light vision decline in monkeys at plasma exposuressimilar to the human dose (see section 5.3). An ophthalmological evaluation should be performed annually and at the onset of any new visual disturbances during therapy.

Concomitant use of moderate and strong CYP3A inducers

Concomitant use of moderate and strong CYP3A inducers may reduce the efficacy of lonafarnib and they should be avoided (see section 4.5).

Concomitant use of moderate CYP3A inhibitors

Concomitant use of lonafarnib and moderate CYP3A inhibitors should be avoided. If concomitant use is unavoidable, the dose of lonafarnib should be reduced by 50% and QTc monitoring is recommended (see sections 4.2 and 4.5).

Concomitant use of weak CYP3A inducers

Concomitant use of weak CYP3A inducers may reduce the efficacy of lonafarnib and should be avoided. If their use is unavoidable, no dose adjustment of lonafarnib is needed (see section 4.5).

Subjects with known dysfunctional polymorphisms in CYP3A4

Subjects with a known dysfunctional polymorphism in CYP3A4 should start therapy at 50% of the indicated dose. QTc monitoring is necessary (see section 4.2 and 4.5).

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 ataxiatelangiectasia.

Excipients with known effect

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

Strong CYP3A inhibitors

When lonafarnib was co-administered with ketoconazole, a strong CYP3A inhibitor, in healthy adult subjects, ketoconazole (200 mg for 5 doses) increased lonafarnib (single dose of 50 mg) C_max by 270% and AUC by 425%. This may lead to an increased risk of adverse reactions. Therefore, concomitant use of lonafarnib and strong CYP3A inhibitors is contraindicated (see section 4.3).

Moderate CYP3A inhibitors

No interaction studies have been conducted with a moderate CYP3A inhibitor. Concomitant use of lonafarnib and a moderate CYP3A inhibitor should be avoided (see sections 4.2 and 4.4).

Select HMG-CoA reductase inhibitors

No interaction studies have been conducted. The HMG-CoA reductase inhibitors atorvastatin, lovastatin and simvastatin are all dependent on CYP3A for metabolism. Lonafarnib is a potent in vivo CYP3A mechanism-based inhibitor and, when given concomitantly with either atorvastatin, lovastatin or simvastatin, is expected to increase the plasma concentrations of these statins. This results in an increased risk of myopathy including rhabdomyolysis. Therefore, concomitant use of lonafarnib and atorvastatin, lovastatin and simvastatin are contraindicated (see section 4.3).

Midazolam

When lonafarnib was co-administered with midazolam in healthy adult subjects, multiple dose lonafarnib (100 mg twice daily for 5 consecutive days) increased midazolam (single 3 mg oral dose) C_max by 180% and AUC by 639%. This interaction thereby increasesthe risk of extreme sedation and respiratory depression. Therefore, concomitant use of lonafarnib and midazolam is contraindicated (see sections 4.2, 4.3 and 4.4).

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 (see section 4.4).

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 (see section 4.4).

Weak CYP3A inducers

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 (see sections 4.2 and 4.4). 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.

Foods and select juices that affect the metabolism of lonafarnib

Grapefruit, cranberries, pomegranate and Seville oranges (e.g., orange marmalade), otherwise known as sour or bitter oranges, inhibit the CYP3A system. Ingestion of food or juices containing these fruits should be avoided while taking lonafarnib (see section 4.2).

Weak CYP3A inhibitors

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 (see sections 4.2 and 6.6).

Loperamide

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 (see section 4.4). 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.

CYP2C19 substrates

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.

MATE1 and MATE2-K

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.

P-glycoprotein substrates

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.

OCT1 substrates

In vitro studies indicate that lonafarnib is an OCT1 inhibitor at clinically relevant systemic concentrations. However, the clinical relevance is currently unknown.

Oral contraceptives

There have been no studies assessing the interaction of concomitant lonafarnib and an oral contraceptive. Females of childbearing potential must use effective contraception during treatment with Zokinvy and for at least 1 week after the final dose (see section 4.6).

Paediatric population

Interaction studies have only been performed in adults.

Women of childbearing potential/Contraception in males and females

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

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

Pregnancy

There are no or limited data from the use of lonafarnib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Lonafarnib is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether lonafarnib is excreted in human milk. Animal studies have shown excretion of lonafarnib in milk (for details see section 5.3). 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.

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 (see section 5.3). 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 (see section 4.8).

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 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.

Table 3. Adverse reactions:

^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 (see section 4.4). 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).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.