NIPENT Powder for solution for injection/infusion Ref.[9111] Active ingredients: Pentostatin

Warnings

Pentostatin should be administered under the supervision of a physician qualified and experienced in the use of cancer chemotherapeutic agents. The use of doses higher than those specified (see Section 4.2) is not recommended. Dose-limiting severe renal, liver, pulmonary, and CNS toxicities occurred in Phase 1 studies that used pentostatin at a higher dose (20-50 mg/m²/course) than recommended.

In a clinical investigation in patients with refractory chronic lymphocytic leukaemia using pentostatin at the recommended dose in combination with fludarabine phosphate, four of six patients entered on the study had severe or fatal pulmonary toxicity. The use of pentostatin in combination with fludarabine phosphate is not recommended.

Biochemical studies have demonstrated that pentostatin enhances the effects of vidarabine, a purine nucleoside with antiviral activity. The combined use of vidarabine and pentostatin may result in an increase in adverse reactions associated with each drug. The therapeutic benefit of the drug combination has not been established.

Patients with hairy cell leukaemia may experience myelosuppression primarily during the first few courses of treatment. Patients with infections prior to pentostatin treatment have in some cases developed worsening of their condition leading to death; whereas others have achieved complete response. Patients with infection should be treated only when the potential benefit of treatment justifies the potential risk to the patient. Efforts should be made to control the infection before treatment is initiated or resumed.

In patients with progressive hairy cell leukaemia, the initial courses of pentostatin treatment were associated with worsening of neutropaenia. Therefore, frequent monitoring of complete blood counts during this time is necessary. If severe neutropenia continues beyond the initial cycles, patient should be evaluated for disease status, including a bone marrow examination.

Pentostatin might have harmful effects on the genotype. Therefore, it is recommended that men undergoing treatment with pentostatin should not father a child during treatment up to 6 months thereafter. Contraception is to be guaranteed for women of childbearing age. Should a pregnancy occur during treatment, the possibility of a genetic consultation is to be considered.

Bone Marrow Transplant Regimen with high dose cyclophosphamide

Acute pulmonary oedema and hypotension leading to death, have been reported in the literature in patients treated with pentostatin in combination with carmustine, etoposide and high dose cyclophosphamide as part of an ablative regimen for bone marrow transplant. The combination of pentostatin and high dose cyclophosphamide is not recommended.

Elevations in liver function tests occurred during treatment with pentostatin and were generally reversible.

Renal toxicity was observed at higher doses in early studies; however, in patients treated at the recommended dose, elevations in serum creatinine were usually minor and reversible. There were some patients who began treatment with normal renal function who had evidence of mild to moderate toxicity at a final assessment. (See Administration to Patient [4.2].)

Rashes, occasionally severe, were commonly reported and may worsen with continued treatment. Withholding of treatment may be required. (See Administration to Patient [4.2].)

Extra care should be taken in treating patients beginning therapy with poor performance.

Precautions

Therapy with pentostatin requires regular patient observation and monitoring of haematologic parameters and blood chemistry values. If severe adverse reactions occur, the drug should be withheld (see Administration to Patient [4.2]) and appropriate corrective measures should be taken according to the clinical judgement of the physician.

Pentostatin treatment should be withheld or discontinued in patients showing evidence of nervous system toxicity.

Prior to initiating therapy with pentostatin, renal function should be assessed with a serum creatinine and/or a creatinine clearance assay. (See Pharmacokinetic Properties [5.2], Administration to Patient [4.2].) Complete blood counts, serum creatinine, and BUN should be performed before each dose of pentostatin and at appropriate periods during therapy. Severe neutropenia has been observed following the early courses of treatment with pentostatin and therefore frequent monitoring of complete blood counts is recommended during this time. If haematologic parameters do not improve with subsequent courses, patients should be evaluated for disease status, including a bone marrow examination. Periodic monitoring of the peripheral blood for hairy cells should be performed to assess the response to treatment.

In addition, bone marrow aspirates and biopsies may be required at 2 to 3 month intervals to assess the response to treatment.

Allopurinol

Allopurinol and pentostatin are both associated with skin rashes. Based on clinical studies in 25 refractory patients who received both pentostatin and allopurinol, the combined use of pentostatin and allopurinol did not appear to produce a higher incidence of skin rashes than observed with pentostatin alone. There has been a report of one patient who received both drugs and experienced a hypersensitivity vasculitis that resulted in death. It was unclear whether this adverse event and subsequent death resulted from the drug combination.

Vidarabine

Biochemical studies have demonstrated that pentostatin enhances the effects of vidarabine, a purine nucleoside with antiviral activity. The combined use of vidarabine and pentostatin may result in an increase in adverse reactions associated with each drug. The therapeutic benefit of the drug combination has not been established.

Fludarabine

The combined use of pentostatin and fludarabine phosphate is not recommended because it has been associated with an increased risk of fatal pulmonary toxicity. (See Section 4.4, Warnings.)

Bone Marrow Transplant Regimen with high dose cyclophosphamide

Acute pulmonary oedema and hypotension leading to death, have been reported in the literature in patients treated with pentostatin in combination with carmustine, etoposide and high dose cyclophosphamide as part of an ablative regimen for bone marrow transplant. The combination of pentostatin and high dose cyclophosphamide is not recommended.

Women of childbearing potential receiving pentostatin should be advised not to become pregnant.

No fertility studies have been conducted in animals. Incompletely reversible seminiferous tubular atrophy and degeneration in rats and in dogs may be indicative of potential effects on male fertility. The possible adverse effects on human fertility have not been determined.

There are no data from the use of pentostatin in pregnant patients. Studies in animals have shown reproductive toxicity. Pentostatin has been shown to be teratogenic in rodent studies. Pentostatin is not recommended in pregnancy and women of child bearing potential not using effective contraception. If the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazards to the foetus.

It is not known whether pentostatin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from pentostatin in nursing infants, nursing is not recommended.

Pentostatin has a minor or moderate influence on the ability to drive and use machines. Patients should be advised to use caution in driving or using machinery following drug administration.

Pentostatin is lymphotoxic. Aside from myelosuppression, pentostatin is immunosuppressive in particular by suppression of the CD4+ lymphocyte subset. CD4+ counts smaller than 200 per µl are usually seen during treatment with pentostatin and CD4+ count suppression can outlast the end of treatment by more than 6 months. With the exception of frequent herpes zoster infections the clinical consequences of the suppression of CD4+ counts in hairy cell leukaemia are not well understood yet. Long term consequences are not predictable, but currently there is no evidence for higher frequency of secondary malignancies.

The following adverse events were reported during clinical studies in patients with hairy cell leukaemia who were refractory to alpha-interferon or were treated as front-line therapy. Most patients experienced an adverse event. The most commonly reported reactions were nausea and/or vomiting or leucopenia, each occurring in about 60% of patients. Fever, rash and fatigue were reported in about 40% of patients. Most adverse events were either mild or moderate diminished in frequency with continued therapy. Twelve percent of patients withdrew from treatment due to an adverse event. Many hairy cell leukaemia patients experience adverse events while under therapy with pentostatin. Given the natural history of the disease and the pharmacological properties of the drug it may be difficult in certain cases to discriminate between drug-related and disease-related adverse events. No extravasation injuries were reported in clinical studies.

The following adverse reactions have been reported during clinical studies in patients with HCL or during post-authorization use of pentostatin, either as single agent or in combinations with various agents for unapproved indications. They have been listed as Very common (>10%), Common (1-10%), Uncommon (0.1-1%) or Rare (0.01-0.1%).

Infections and Infestations

Very common (>10%): Upper respiratory infection, Rhinitis, Pharyngitis, Viral infection

Common¹ (1-10%): Herpes Zoster, Infection (unspecified), Sinusitis, Cellulitis, Bacterial infection, Pneumonia, Conjunctivitis, Furunculosis, Herpes simplex, Bronchitis, Sepsis, Urinary tract infection, Abscess skin, Oral Candidiasis, Mycotic skin infection, Peri-anal abscess, E. Coli pneumonia, Fungal pneumonia, Septic shock, Staphylococcal infection, Urosepis, Osteomyelitis

Uncommon² (0.1-1%): Acute gastroenteritis, Pulmonary Aspergillosis, Clostridium Difficile colitis, Cystitis, Cytomegalovirus infection

Rare² (0.01-0.1%): Oesophageal candidiasis

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Common¹ (1-10%): Neoplasms, Skin carcinoma

Uncommon² (0.1-1%): Tumor lysis syndrome

Blood and Lymphatic System Disorders

Very common (>10%): Leucopenia, thrombocytopenia, Anaemia, Blood disorder, Eosinophilia, Hypochromic anaemia, Pancytopenia

Common¹ (1-10%): Agranulocytosis, Acute leukaemia, Febrile neutropenia, Ecchymosis, Lymphadenopathy, Splenomegaly

Uncommon² (0.1-1%): Pure red cell aplasia, Autoimmune haemolytic anaemia, Anaemia-Haemolytic, Aplastic anaemia haemolytic uremic syndrome, Idiopathic thrombocytopenia purpura, Thrombotic thrombocytopenia purpura.

Rare² (0.01-0.1%): Autoimmune thrombocytopenia

Immune System Disorders

Very common (>10%): Allergic reaction

Common¹ (1-10%): Graft versus Host Disease³

Uncommon² (0.1-1%): Graft failure

Rare² (0.01-0.1%): Anaphylaxis

Metabolism and Nutrition Disorders

Common¹ (1-10%): Dehydration, Gout, Electrolyte imbalance, Hypercalcaemia, Hyponatraemia, Hyperglycaemia, Weight increased, Weight decreased, LDH increased

Uncommon² (0.1-1%): Hyperkalaemia, Hypokalaemia, Oxygen saturation decreased

Rare² (0.01-0.1%): Fluid overload, Hypocalcaemia

Psychiatric disorders

Common¹ (1-10%): Anxiety, Depression, Nervousness, Abnormal dreams, Decrease/loss libido, Emotional lability, Hallucination, Hostility, Neurosis, Thinking abnormal, Depersonalisation

Nervous System Disorders

Very common (>10%): Headache, Neurotoxicity

Common¹ (1-10%): Confusion, Dizziness, Insomnia, Paraesthesia, Somnolence, Amnesia, Ataxia, Convulsions, Dysarthria, Dysgeusia, Encephalitis, Hyperkinesia, Meningism, Neuralgia, Neuritis, Neuropathy, Paralysis, Syncope, Twitching, Tremor, Vertigo, Hypaesthesia

Rare² (0.01-0.1%): Dementia Alzheimer’s (suspected), Grand mal convulsion, Migraine, Parkinson’s disease (aggravated), Petit mal epilepsy

Eye Disorders

Common¹ (1-10%): Dry eyes, Lacrimal disorder, Photophobia, Retinopathy, Vision abnormal, Fixed pupil, Lacrimation increased, Eye pain

Rare² (0.01-0.1%): Blepharitis

Very rare: Unilateral uveitis with vision loss

Ear and Labyrinth Disorders:

Common¹ (1-10%): Deafness, Ear pain, Labyrinthitis, Tinnitus

Cardiac Disorders

Common¹ (1-10%): Angina pectoris, Arrhythmia, A-V block, Bradycardia, Extrasystoles ventricular, Heart arrest, Heart failure, Pericardial effusion, Sinus arrest, Tachycardia, Atrial fibrillation, Cardiac failure congestive, Flushing, Abnormal electrocardiogram.

Uncommon² (0.1-1%): Cardiomyopathy, Myocardial infarction

Rare² (0.01-0.1%): Pericarditis; Decreased ejection fraction

Vascular Disorders

Common¹ (1-10%): Haemorrhage, Hypotension, Hypertension, Deep thrombophlebitis, Phlebitis, Vasculitis

Uncommon² (0.1-1%): Capillary leak syndrome

Rare² (0.01-0.1%): Shock

Respiratory, Thoracic and Mediastinal Disorders

Very common (>10%): Coughing, Lung disorder

Common¹ (1-10%): Asthma, Dyspnoea, Laryngeal oedema, Lung oedema, Pulmonary embolism, Epistaxis

Uncommon² (0.1-1%): Adult respiratory distress syndrome, Acute respiratory failure, Bronchospasm, Pleural effusion, Pneumothorax, Respiratory tract haemorrhage, Wheezing

Rare² (0.01-0.1%): Alveolitis, Alveolitis fibrosing, Cryptogenic organizing pneumonia, Diffuse alveolar damage, Obstructive airway disease, Pulmonary alveolar haemorrhage

Gastrointestinal Disorders

Very common (>10%): Nausea and/or vomiting; Diarrhoea, Abdominal pain, Anorexia, Rectal disorder, Rectal haemorrhage

Common¹ (1-10%): Dental Disorder, Dyspepsia, Gingivitis, Stomatitis, Constipation, Dysphagia, Flatulence, Glossitis, Ileus, Dry mouth

Uncommon² (0.1-1%): Acute enteritis

Hepato-biliary disorders

Very common (>10%): LFT increased, jaundice, hyperbilirubinaemia, ALT increased, AST increased

Skin and Subcutaneous Tissue Disorders

Very common (>10%): Rash, Pruritus, Sweating, Skin disorder, Maculopapular rash

Common¹ (1-10%): Dry skin, Urticaria, Acne, Alopecia, Eczema, Petechial Rash, Photosensitivity reaction, Exfoliative dermatitis, Skin discoloration, Dermatitis bullous, Seborrhoea

Uncommon² (0.1-1%): Angioneurotic oedema

Rare: Pemphigus, Stevens-Johnsons’s syndrome

Musculoskeletal and Connective Tissue Disorders

Very common (>10%): Myalgia, Bone disorder, Arthropathy

Common¹ (1-10%): Arthralgia, Arthritis

Uncommon² (0.1-1%): Pain in extremities

Renal and Urinary Disorders

Very common (10%): Genito-urinary disorder, BUN increased

Common¹ (1-10%): Creatinine increased, Renal impairment, Nephropathy, Renal failure, Nephrolithiasis, Acute renal failure, Dysuria, Urinary retention

Uncommon² (0.1-1%): Cystitis haemorrhagic

Reproductive system and breast disorders

Common¹ (1-10%): Amenorrhoea, Breast mass, Erectile dysfunction

General Disorders and Administration Site Conditions

Very common (>10%): Fever, fatigue, chills, asthenia, pain

Common¹ (1-10%): Chest pain, Death, Face oedema, Peripheral oedema, Flu-like symptoms, Hangover, Back pain, Malaise

Uncommon² (0.1-1%): Mucositis, Multiorgan failure

Rare² (0.01-0.1%): Systemic inflammatory response syndrome, Lower extremity tenderness

¹ Includes all events which occurred in less than 3% of NIPENT-treated patients during the initial phase of the SWOG study:
² Based on 1549 patients included in post-marketing studies through Oct 10, 2005.
³ Reported only in GVHD studies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 Yellow Card Scheme at: Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Acidic solutions should be avoided (the pH of the reconstituted powder is 7.0 to 8.2).