Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: TMC Pharma (EU) Limited, G24A ArcLabs Research & Innovation Centre, Carriganore, Waterford, X91 P20H, Ireland
Hypersensitivity to the active substance or any other member of the farnesyltransferase class, or to any of the excipients listed in section 6.1.
Concomitant use with strong CYP3A inhibitors (see section 4.5).
Concomitant use of medicinal products that are predominantly metabolised by CYP3A4, such as midazolam, atorvastatin, lovastatin and simvastatin (see sections 4.2, 4.4 and 4.5).
Patients with severe hepatic impairment (Child-Pugh Class C) (see section 5.2).
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.
Lonafarnib has been shown to prolong cardiac ventricular repolarisation, as measured by the QTc interval on the surface ECG, in a concentration-dependent manner in adult healthy volunteers. QTc interval prolongation increases the risk of Torsade de pointes, other serious arrhythmias, and sudden death. At subtherapeutic exposures, QTc interval prolongation up to 20 ms has been observed (see section 5.1).
Based on this finding, use of lonafarnib should be avoided in patients with a history of cardiac arrhythmias or with conditions that increase the risk of Torsade de pointes or sudden death, such as long QT syndrome, symptomatic bradycardia, hypokalaemia, hypomagnesemia or congestive heart failure. Significant QTc interval prolongation can occur when lonafarnib is taken with strong CYP3A4 inhibitors or other drugs known to prolong the QTc interval (see section 4.5). This risk may be exacerbated in the presence of hypokalaemia or hypomagnesaemia, further increasing the potential for life-threatening arrhythmias.
ECGs and serum electrolytes should be assessed before starting lonafarnib and monitored throughout lonafarnib treatment, with any electrolyte imbalances corrected promptly.
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).
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.
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.
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.
Lonafarnib caused rod-dependent, low-light vision decline in monkeys at plasma exposures similar 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 may reduce the efficacy of lonafarnib and they should be avoided (see section 4.5).
Concomitant use of lonafarnib and strong CYP3A inhibitors is contraindicated (see section 4.3 and 4.5).
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 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).
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.
Zokinvy contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.
Lonafarnib is metabolised by CYP3A4 and 3A5 and is also known to be a moderate CYP3A4 inhibitor. Hence, it autoinhibits its metabolism. There is an approximately 4-fold increase in Cmax following multiple doses of lonafarnib (75 mg twice daily for 6 days) relative to single-dose lonafarnib (75 mg). Based on the Cmax and AUC values, an accumulation of the active substance at steady state was evident. The same was true for the main metabolite of lonafarnib but with a reduced magnitude.
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) Cmax by 3.7-fold and AUC by 5.3-fold. 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).
When fluconazole (200 mg once daily for 4 days), a moderate CYP3A4 inhibitor, is added to a multiple-dose lonafarnib regimen (75 mg twice daily for 6 days then co-administered with fluconazole for 4 days), differences in lonafarnib exposures are not considered clinically relevant (no change in Cmax and a 1.2-fold decrease in AUC). No further inhibition besides the autoinhibitory effect following multiple-dose lonafarnib is observed when adding the moderate CYP3A4 inhibitor fluconazole to the regimen. However, adding lonafarnib to an existing regimen containing a moderate CYP3A inhibitor requires caution, and a lower starting dose might be reasonable (see sections 4.2 and 4.4).
No drug-drug 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).
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 days resulted in the Cmax of lonafarnib being reduced by 12.5-fold and the AUC being reduced by 50-fold, 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).
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).
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.
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).
Lonafarnib is an inhibitor of CYP3A4. When lonafarnib was co-administered with CYP3A4 substrate midazolam in healthy adult subjects, multiple-dose lonafarnib (100 mg twice daily for 5 consecutive days) increased midazolam (single 3 mg oral dose) Cmax by 2.8-fold and AUC by 7.4-fold. This interaction thereby increases the 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).
No interaction studies have been conducted with HMG-CoA reductase inhibitors. 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, lonafarnib 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).
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) Cmax by 3.1-fold and AUC by 4.0-fold. 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.
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) Cmax 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.
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.
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) Cmax 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.
In vitro studies indicate that lonafarnib is an OCT1 inhibitor at clinically relevant systemic concentrations. However, the clinical relevance is currently unknown.
Lonafarnib should be used with caution in patients who have or may develop prolongation of the QT interval, including those patients taking anti-arrhythmic medicinal products such as amiodarone, disopyramide, procainamide, quinidine and sotalol or other medicinal products that may lead to QT prolongation such as chloroquine, halofantrine, clarithromycin, haloperidol, methadone and moxifloxacin (see section 4.4). This is not an exhaustive list, and all anti-arrhythmic medications should be evaluated for potential QT prolongation activity.
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).
Interaction studies have only been performed in adults.
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.
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.
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.
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).
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%).
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:
| System organ class | Very common | Common |
| Infections and infestations | Upper respiratory tract infection | Infection Rhinitis Gastroenteritis Influenza Oral pustule Perirectal abscess Pneumonia Sinusitis |
| Blood and lymphatic system disorders | Haemoglobin decreased | White blood cell count decreased |
| Metabolism and nutrition disorders | Decreased appetite Weight decreased | Dehydration Hypermagnesaemia Hypokalaemia Hypoalbuminaemia Hyponatraemia |
| Psychiatric disorders | Depressed mood | |
| Nervous system disorders | Cerebral ischaemia Headache Dizziness Paraesthesia | |
| Respiratory, thoracic and mediastinal disorders | Cough Epistaxis Laryngeal/oropharyngeal pain Nasal congestion | |
| Gastrointestinal disorders | Vomiting Diarrhoea Nausea Abdominal paina Constipation | Flatulence Colitis Dyspepsia Gastritis Lower gastrointestinal haemorrhage |
| Hepatobiliary disorders | Aspartate aminotransferase increased Alanine aminotransferase increased Blood bicarbonate decreased | Blood creatinine decreased |
| Skin and subcutaneous tissue disorders | Rash Pruritus Dry skin Skin hyperpigmentation | |
| Musculoskeletal and connective tissue disorders | Musculoskeletal pain Back pain Pain in extremity | |
| General disorders and administration site conditions | Fatigue | Fever Chest pain Chills |
| Injury, poisoning and procedural complications | Tooth fracture |
a Abdominal pain includes abdominal pain and abdominal pain upper
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 (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).
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 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.
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