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Dovprela (Previously Pretomanid FGK) is a brand name for Pretomanid. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Dovprela is indicated in combination with bedaquiline, linezolid and moxifloxacin for the treatment of − adults with pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant to rifampicin, with or without resistance to isoniazid. Dovprela is indicated in combination with bedaquiline and linezolid for…
Verbatim from this product's EMA label. Tap a section to expand.
Treatment with pretomanid should be initiated and monitored by a physician experienced in the management of TB due to drug-resistant M. tuberculosis. Pretomanid should be administered by directly observed therapy (DOT) or in accordance with local practice.
Posology The recommended dosage is 200 mg (one tablet) pretomanid once daily, for 26 weeks. 3 Pretomanid should be administered only in combination with bedaquiline (400 mg once daily for 2 weeks followed by 200 mg 3 times per week [with at least 48 hours between doses] orally for a total of 26 weeks) and linezolid (600 mg daily orally for up to 26 weeks), with or without moxifloxacin (400 mg once daily for 26 weeks).
See also below, on treatment duration. In case of confirmed pulmonary TB resistant to rifampicin and a fluoroquinolone, with or without resistance to isoniazid, pretomanid should be combined with bedaquiline and linezolid, and moxifloxacin should be omitted.
The product information for bedaquiline, linezolid and moxifloxacin should be consulted for additional information on the use of these medicinal products. 1 for details of the study. 1) • If either bedaquiline or pretomanid is discontinued for any reason, the entire combination regimen should be discontinued.
• If linezolid is permanently discontinued during the initial four consecutive weeks of treatment, the entire combination regimen should be discontinued. • If linezolid is discontinued after the initial four weeks of consecutive treatment, the regimen may be continued with only bedaquiline, pretomanid and with or without moxifloxacin.
Missed doses Any missed doses of pretomanid, bedaquiline and moxifloxacin should be made up at the end of treatment. Doses of linezolid that are missed due to linezolid adverse reactions should not be made up at the end of treatment.
Refer to the product information of bedaquiline, linezolid and moxifloxacin for additional information on these medicinal products. Treatment duration The total duration of treatment with pretomanid in combination with bedaquiline, linezolid and with or without moxifloxacin is 26 weeks.
Pretomanid in combination with bedaquiline and linezolid can be extended to a total of 39 weeks. This extension is justified in cases of failure to convert culture between months 4 and 6 while on treatment and it can be based on the clinical judgement of the treating physician.
The most frequent adverse drug reactions (ADRs) during treatment with pretomanid in combination with bedaquiline and linezolid were nausea, vomiting and transaminases increased. Patients experienced peripheral neuropathy and anaemia, which are known adverse reactions to linezolid, respectively.
Nausea, vomiting and transaminases increased are possible adverse reactions to all three medicinal products in the regimen. The most frequent ADRs during treatment with pretomanid in combination with bedaquiline, linezolid and moxifloxacin were transaminases increased and QTc prolongation.
Refer to the Summary of Product Characteristics of bedaquiline, linezolid and moxifloxacin for more information on adverse reactions caused by these medicinal products. Tabulated list of pretomanid adverse reactions The table below displays ADRs, by system organ class and frequency, which are considered at least possibly related to the treatment regimens BPaL and BPaLM (Bedaquiline, Pretomanid, Linezolid and Moxifloxacin) and have been observed during the following clinical trials: • Nix-TB: 109 patients treated with pretomanid in combination with bedaquiline and linezolid (1 200 mg daily) for 26 weeks • ZeNix: 45 patients treated with pretomanid in combination with bedaquiline and linezolid (1 200 mg daily) for 26 weeks and 45 patients treated with pretomanid in combination with bedaquiline and linezolid (600 mg daily) • TB-PRACTECAL: 273 patients treated with pretomanid in combination with bedaquiline, linezolid (600 mg) with or without moxifloxacin (400 mg) for 24 weeks (N=151 patients in BPaLM arm + N=122 patients in BPaL arm) The ADR list below reflects in part the safety profile of the study regimens as it is hard to separate causality of one drug from another.
An overall population of 472 patients receiving BPaL regimen with or without moxifloxacin has been included. ADRs considered attributed to linezolid are marked with Δ. 8 ADRs attributed to moxifloxacin are marked with §.
Safety and effectiveness of pretomanid have not been established for its use in combination with medicinal products other than bedaquiline, linezolid and with or without moxifloxacin as part of the recommended dosing regimen, and thus pretomanid should not be used as part of any other regimen.
Hepatotoxicity Hepatotoxicity may occur with use of the regimen consisting of pretomanid, bedaquiline, linezolid and with or without moxifloxacin. Liver-related laboratory tests should be monitored. 1), should be avoided while on the regimen, especially in patients with impaired hepatic function.
Symptoms and signs (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness and hepatomegaly) should be addressed throughout treatment. Laboratory tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin) should be monitored at initiation of treatment, and at a minimum once every week during the first month of treatment, every other week during month 2, and monthly thereafter while on treatment, and as needed.
If evidence of new or worsening liver dysfunction occurs, a test for viral hepatitis should be performed and other hepatotoxic medicinal products should be discontinued. Treatment with the entire regimen should be interrupted if: • Aminotransferase elevations are accompanied by total bilirubin elevation greater than 2 times the upper limit of normal.
• Aminotransferase elevations are greater than 8 times the upper limit of normal. • Aminotransferase elevations are greater than 5 times the upper limit of normal and persist beyond 2 weeks. Treatment may be re-initiated under close surveillance when hepatic enzymes and clinical symptoms normalize.
Modification/interruption due to linezolid adverse reactions Modification or interruption of linezolid dosing may be needed during the course of therapy to manage the known linezolid toxicities. 1). Myelosuppression Complete blood counts should be monitored at a minimum at start of treatment, at two weeks, and then monthly in patients receiving linezolid as part of the combination regimen.
1.
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1). Elderly population (≥ 65 years of age) There is limited clinical data on the use of pretomanid in elderly patients. Hence, the safety and efficacy of pretomanid in elderly patients have not been established. 4). Renal impairment The safety and efficacy of pretomanid in populations with renal impairment have not been established.
No data are available. Use in patients with renal impairment is not recommended. Paediatric population The safety and efficacy of pretomanid in children and adolescents have not yet been established. No data are available. Method of administration 4 For oral use.
2). Tablets should be swallowed with water. If the patient has trouble swallowing a whole tablet, crushing the tablets and mixing with water for administration may be an acceptable alternative. Intake should occur immediately after crushing and mixing with water.
Table 1:
Adverse Drug Reactions from Clinical Studies System Organ Class Very Common ≥1/10 Common ≥1/100 to <1/10 Uncommon ≥1/1,000 to <1/100 Infections and infestations Vulvovaginal candidiasis§, oral candidiasis* Blood and lymphatic system disorders Leukopenia* ∆, anaemia* ∆, lymphopenia ∆ Neutropenia* ∆, eosinophilia, thrombocytopenia* ∆ Pancytopenia ∆ Metabolism and nutrition disorders Hyponatraemia Δ, hypernatraemia Δ, hypocalcaemia, hypoalbuminaemia Δ, hyperkalaemia § Δ, hypokalaemia Δ, decreased appetite, hyperglycaemia § Δ, hypoglycaemia, lactic acidosis* ∆, hypomagnesaemia Dehydration, hypovolaemia, Psychiatric disorders Depression, insomnia Anxiety Nervous system disorders Headache, peripheral neuropathy* ∆, Dysgeusia, dizziness, tremor § Eye disorders Visual impairment* Lens disorder, eye pruritis, eye swelling, papilloedema, presbyopia, eye irritation, eye pain*, optic neuropathy*∆, cataract Ear and labyrinth disorders Deafness* Cardiac disorders Palpitations Sinus bradycardia, sinus tachycardia Vascular disorders Hypertension* Hypotension Respiratory, thoracic and mediastinal disorders Haemoptysis, epistaxis Cough* Gastrointestinal disorders Nausea, vomiting, Gastritis*, diarrhoea, constipation, pancreatitis, abdominal pain*, dyspepsia Gastrooesophageal reflux disease, abdominal distension, glossodynia, haematemesis, eructation 9 System Organ Class Very Common ≥1/10 Common ≥1/100 to <1/10 Uncommon ≥1/1,000 to <1/100 Hepatobiliary disorders Transaminase increased* Hyperbilirubinaemia Hepatomegaly, jaundice Immune system disorders Hypersensitivity Skin and subcutaneous tissue disorders Rash* Acne*, dry skin, , pruritus*, urticaria Alopecia, dermatitis allergic, erythema, skin hyperpigmentation, angioedema Musculoskeletal and connective tissue disorders Musculoskeletal pain* Muscle spasms* Polyarthritis* General disorders and administration site conditions Chest pain*, fatigue* Investigations Electrocardiogram QT prolonged Gamma- glutamyltransferase increased, , blood alkaline phosphatase increased, blood urea increased, lipase increased*, amylase increased*, blood creatinine increased § Δ, creatinine renal clearance decreased Blood creatine phosphokinase increased, albumin urine present, blood creatine phosphokinase MB increased, blood uric acid increased, *Selected terms are collapsed as follows: leukopenia (leukopenia, white blood cell count decreased); lymphopenia (lymphopenia, lymphocyte count decreased); peripheral neuropathy (burning sensation, hypoesthesia, hyporeflexia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, polyneuropathy); gastritis (gastritis, chronic gastritis); acne (acne, dermatitis acneiform); musculoskeletal pain (arthralgia, back pain, costochondritis, myalgia, pain in extremity, musculoskeletal pain, muscle strain); transaminases increased (alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, liver function test increased, transaminases increased); rash (rash, rash erythematous, rash maculo-papular, rash papular, rash vesicular, rash pustular, nodular rash); pruritus (pruritus, pruritus generalized, rash pruritic); abdominal pain (abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort); visual impairment (vision blurred, visual acuity reduced, visual impairment); amylase increased (amylase increased, hyperamylasaemia); lipase increased (hyperlipasaemia, lipase increased); optic neuropathy (optic neuropathy, optic neuritis); pancreatitis (pancreatitis, haemorrhagic pancreatitis); anaemia (anaemia, haemoglobin decreased); thrombocytopenia (thrombocytopenia, platelet count decreased); neutropenia (neutropenia, neutrophil count decreased); hyperbilirubinemia (hyperbilirubinemia, blood bilirubin increased); lactic acidosis (lactic acidosis, acidosis, blood lactic acid increased, blood lactate increased); muscle […]
Haematologic parameters are variable from measurement to measurement, and decreases should be evaluated in the context of the patient’s overall medical condition. Guidelines below may be considered when it is likely that linezolid has caused the decrease in blood count.
Consider pausing or reducing the dose of linezolid to 300 mg in the following situations. • Anaemia - if haemoglobin falls below 80 g/l or more than 25% below the start of treatment. 75 × 109/l or significantly below baseline. Confirm with a repeat test before making further decisions as ANCs can have diurnal and other variability.
• Thrombocytopenia - if platelets fall below 50 × 109/l or significantly below baseline. Ideally confirm with a repeat test before making further decisions. When improvement in the myelosuppression is observed, consider resuming linezolid at the initial dose or at half the initial dose.
Peripheral neuropathy and optic neuropathy Peripheral neuropathy associated with linezolid is generally reversible or improved with interruption, dose reduction, or discontinuation of linezolid dosing. When improvement in the peripheral neuropathy is observed, consider resuming linezolid at 300 mg (half the initial dose).
1), the incidence of interruption/reduction/discontinuation of linezolid due to peripheral neuropathy increased steadily from around 2 months of therapy throughout the completion of therapy. Monitor visual symptoms in all patients receiving the combination regimen of pretomanid, bedaquiline, linezolid and with or without moxifloxacin.
If a patient experiences symptoms of visual impairment, interrupt linezolid dosing and obtain prompt ophthalmologic examination to evaluate for signs of optic neuropathy. Lactic acidosis Lactic acidosis is a known adverse reaction of linezolid.
Patients who develop recurrent nausea or vomiting should receive immediate medical evaluation, including evaluation of bicarbonate and lactic acid levels, and interruption of linezolid should be considered. Linezolid may be reinitiated at a lower dose with close monitoring when signs and symptoms of lactic acidosis resolve.
QT prolongation QT prolongation was reported with the combination regimen of pretomanid, bedaquiline, linezolid and with or without moxifloxacin. QT prolongation is a known adverse reaction of bedaquiline and moxifloxacin. Bedaquiline in combination with pretomanid appears to result in a higher QT prolongation than expected with bedaquiline alone.
However, the impact of pretomanid has not been fully characterized. An ECG should be obtained before initiation of treatment, and at least monthly during treatment with the combination regimen of pretomanid, bedaquiline, linezolid and with or without moxifloxacin.
Serum potassium, calcium, and magnesium should be obtained at baseline and corrected if abnormal. Follow-up monitoring of electrolytes should be performed if QT prolongation is detected. The following may increase the risk for QT prolongation: • a history of Torsade de Pointes, • a personal or family history of congenital long QT syndrome, • a history of or ongoing hypothyroidism, • ongoing bradyarrhythmia, • heart failure or known structural heart disease, • QT-interval as corrected by the Fridericia method (QTcF) > 450 ms (confirmed by repeat electrocardiogram) or • serum calcium, magnesium, or potassium levels below the lower limits of normal.
The entire regimen of pretomanid, bedaquiline, linezolid and with or without moxifloxacin must be discontinued if the patient develops clinically […]