Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Hepatic function
Elevated transaminases have been commonly reported in patients treated with Esbriet. Liver function tests (ALT, AST and bilirubin) should be performed prior to the initiation of treatment with Esbriet, and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter (see section 4.8).

If a patient exhibits an aminotransferase elevation >3 to <5 x ULN without bilirubin elevation and without symptoms or signs of drug-induced liver injury after starting Esbriet therapy, other causes should be excluded, and the patient monitored closely. Discontinuation of other medicines associated with liver toxicity should be considered. If clinically appropriate, the dose of Esbriet should be reduced or interrupted. Once liver function tests are within normal limits Esbriet may be re-escalated to the recommended daily dose if tolerated.

Drug-induced liver injury
Uncommonly, elevations in AST and ALT were associated with concomitant bilirubin increases.
Cases of severe drug-induced liver injury, including isolated cases with fatal outcome, have been reported post-marketing (see section 4.8).

In addition to the recommended regular monitoring of liver function tests, prompt clinical evaluation and measurement of liver function tests should be performed in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.

If a patient exhibits an aminotransferase elevation >3 to <5 x ULN accompanied by hyperbilirubinaemia or clinical signs or symptoms indicative of liver injury, Esbriet should be permanently discontinued and the patient should not be rechallenged.

If a patient exhibits an aminotransferase elevation to ≥5 x ULN, Esbriet should be permanently discontinued and the patient should not be rechallenged.

Hepatic impairment
In subjects with moderate hepatic impairment (i.e. Child-Pugh Class B), pirfenidone exposure was increased by 60%. Esbriet should be used with caution in patients with pre-existing mild to moderate hepatic impairment (i.e. Child-Pugh Class A and B) given the potential for increased pirfenidone exposure. Patients should be monitored closely for signs of toxicity especially if they are concomitantly taking a known CYP1A2 inhibitor (see sections 4.5 and 5.2). Esbriet has not been studied in individuals with severe hepatic impairment and Esbriet must not be used in patients with severe hepatic impairment (see section 4.3).

Photosensitivity reaction and rash
Exposure to direct sunlight (including sunlamps) should be avoided or minimised during treatment with Esbriet. Patients should be instructed to use a sunblock daily, to wear clothing that protects against sun exposure, and to avoid other medicinal products known to cause photosensitivity. Patients should be instructed to report symptoms of photosensitivity reaction or rash to their physician. Severe photosensitivity reactions are uncommon. Dose adjustments or temporary treatment discontinuation may be necessary in mild to severe cases of photosensitivity reaction or rash (see section 4.2).

Severe skin reactions
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported post-marketing in association with Esbriet treatment. If signs and symptoms suggestive of these reactions appear, Esbriet should be withdrawn immediately. If the patient has developed SJS, TEN or DRESS with the use of Esbriet, treatment with Esbriet must not be restarted and should be permanently discontinued.

Angioedema/Anaphylaxis
Reports of angioedema (some serious) such as swelling of the face, lips and/or tongue which may be associated with difficulty breathing or wheezing have been received in association with use of Esbriet in the post-marketing setting. Reports of anaphylactic reactions have also been received. Therefore, patients who develop signs or symptoms of angioedema or severe allergic reactions following 3
administration of Esbriet should immediately discontinue treatment. Patients with angioedema or severe allergic reactions should be managed according to standard of care. Esbriet must not be used in patients with a history of angioedema or hypersensitivity due to Esbriet (see section 4.3).

Dizziness
Dizziness has been reported in patients taking Esbriet. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination (see section 4.7). In clinical studies, most patients who experienced dizziness had a single event, and most events resolved, with a median duration of 22 days. If dizziness does not improve or if it worsens in severity, dose adjustment or even discontinuation of Esbriet may be warranted.

Fatigue
Fatigue has been reported in patients taking Esbriet. Therefore, patients should know how they react to this medicinal product before they engage in activities requiring mental alertness or coordination (see section 4.7).

Weight loss
Weight loss has been reported in patients treated with Esbriet (see section 4.8). Physicians should monitor patient’s weight, and when appropriate encourage increased caloric intake if weight loss is considered to be of clinical significance.

Hyponatraemia
Hyponatraemia has been reported in patients treated with Esbriet (see section 4.8). As the symptoms of hyponatraemia may be subtle and masked by the presence of concomitant morbidities, regular monitoring of the relevant laboratory parameters is recommended, especially in the presence of evocative signs and symptoms such as nausea, headache or dizziness.

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

Effects on Driving

4.7   Effects on ability to drive and use machines
Esbriet may cause dizziness and fatigue, which could have a moderate influence on the ability to drive or use machines, therefore patients should exercise caution when driving or operating machinery if they experience these symptoms.