New Safety Labelling Changes Approved By FDA Center for Drug Evaluation and Research

The changes concern lenalidomide, nilotinib and docetaxel

In September 2014, the USA Food and Drug Administration (FDA) Center for Drug Evaluation and Research released new safety labeling changes to the boxed warning, contrindications, warnings, precautions, adverse reactions, or patient package insert/medication guide for several drug products. In term of anticancer agents, new changes concern lenalidomide, nilotinib and docetaxel.

Lenalidomide (Revlimid) capsules

New boxed warning concerns significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma receiving lenalidomide with dexamethasone. Venous thromboembolic events and arterial thromboses are increased in patients treated with lenalidomide. A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with multiple myeloma.

Patient counselling instructions regarding venous and arterial thromboembolism consider informing patients of the risk of thrombosis including DVT, PE, myocardial infarction, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation.

Nilotinib (Tasigna) capsules

New section for drug interactions has been added: results of study CAMN107A2128 entitled “An open-label, two-period, fixed-sequence study to evaluate the effects of multiple doses of nilotinib on the pharmacokinetics of midazolam in CML patients who are resistant and/or intolerant against at least one prior therapy with a BCR-ABL tyrosine kinase inhibitor.”
Effects of nilotinib on drug metabolising enzymes and drug transport systems: Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, potentially increasing the concentrations of drugs eliminated by these enzymes. In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8 and CYP2C9, and decrease the concentrations of drugs which are eliminated by these enzymes.

Docetaxel injection concentrate (20 mg/1 mL, 80 mg/4 mL, and 140 mg/7 mL)

New warnings and precautions consider:

Eye disorders: Cystoid macular oedema (CME) has been reported in patients treated with docetaxel injection concentrate. Patients with impaired vision should undergo a prompt and comprehensive ophthalmologic examination. If CME is diagnosed, docetaxel injection concentrate treatment should be discontinued and appropriate treatment initiated. Alternative non-taxane cancer treatment should be considered.

Alcohol content: Cases of intoxication have been reported with some formulations of docetaxel due to the alcohol content. The alcohol content in a dose of docetaxel injection concentrate may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimised. Consideration should be given to the alcohol content in docetaxel injection concentrate on the ability to drive or use machines immediately after the infusion.

Each administration of docetaxel injection concentrate at 100 mg/m2 delivers 4.75 g/m2 of ethanol. For a patient with a BSA of 2.0 m2, this would deliver 9.5 grams of ethanol. Other docetaxel products may have a different amount of alcohol.

Adverse reactions: Postmarketing experience with docetaxel

  • Ophthalmologic: Cases of cystoid macular oedema (CME) have been reported in patients treated with docetaxel injection concentrate.
  • Respiratory: dyspnoea, acute pulmonary oedema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis have rarely been reported and may be associated with fatal outcome. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.
  • Metabolism and nutrition disorders: cases of hyponatremia have been reported.

Use of docetaxel in specific populations:

  • Pregnancy - Teratogenic effects: Based on its mechanism of action and findings in animals, docetaxel injection concentrate can cause foetal harm when administered to a pregnant woman. If docetaxel injection concentrate is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with docetaxel injection concentrate.
  • Paediatric use - New section added: The efficacy of docetaxel injection concentrate in paediatric patients as monotherapy or in combination has not been established.
  • Hepatic impairment: The alcohol content of docetaxel injection concentrate should be taken into account when given to patients with hepatic impairment.

Patient counselling information consider explanation to patients the possible effects of the alcohol content in docetaxel injection concentrate, including possible effects on the central nervous system. Patients in whom alcohol should be avoided or minimised should consider the alcohol content of docetaxel injection concentrate. Alcohol could impair their ability to drive or use machines immediately after infusion.