Revision Year: 2015 Publisher: Megapharm Ltd, P.O. Box 514, Hod Hasharon, 4510501, Israel Manufacturer: Paesel + Lorei GmbH & Co. KG, Rheinberg, Germany
In immunocompromised patientsImpavido may only be used afterfailure ofstandard therapy as only limited experience is available on therapeutic use of Impavido in such patients.
In 39 HIV co-infected patients with a mean body weight of 59 kg (range 43-99 kg) Impavido was used at a dosage of 100 mg per day for treatment of visceral Leishmaniasisthat wasrecurrent after or refractory to drug therapy. After a mean treatment duration of 55 days(median: 30 days, range 4-732 days) 25 patients(65%) responded to therapy; of these, 16 patients (43 %)showed negative parasitology. 22 patientsreceived atleast one further treatment course with similarresponse rate and tolerability.
The results of a clinicalstudy in cutaneous Leishmaniasis caused by Leishmania brasiliensisindicate, that the efficacy of Impavido against this pathogen may be somewhat lowerthan against other Leishmaniaspecies.
Patients with rare hereditary problems of galactose intolerance,the Lapp lactase deficiency or glucose-galactose malabsorption should nottake this medicine.
Miltefosine may cause fetal harm. Embryo-fetal toxicity, including death and teratogenicity, was observed in animals administered miltefosine prior to mating, during early pregnancy, and during organogenesis at doses lower than the maximum recommended human dose (MRHD). Do not use Impavido in pregnant women. Obtain a urine or serum pregnancy test prior to prescribing Impavido to females of reproductive potential. Advise females of reproductive potential to use effective contraception during IMPAVIDO therapy and for 5 months after completion of therapy
Data should be collected regarding pregnancy outcomes for 10 years after approval of Impavido (Miltefosine) in women who become pregnant while taking Impavido (Miltefosine) or during 5 months after end of Impavido (Miltefosine) therapy.
Miltefosine caused impaired fertility in rats and reversible follicular atresia and diestrus in dogs at doses approximately 1.0 and 0.2 times respectively the MRHD based on body surface area comparisons Impavido. The efficacy of Impavido in the treatment of other Leishmania species has not been evaluated. Effects on human female fertility have not been formally studied.
Miltefosine caused reduced viable sperm counts and impaired fertility in rats at doses approximately 0.4 times the MRHD. A higher dose in rats, approximately 1.0 times the MRHD, caused testicular atrophy and impaired fertility that did not fully reverse 10 weeks after drug administration ended.
Scrotal pain and decreased or absent ejaculation during therapy have been reported during Impavido therapy. The effects of Impavido on human male fertility have not been adequately studied.
Data should be collected regarding the effects of Impavido (Miltefosine) on spermatogenesis and male hormones in patients with leishmaniasis receiving Impavido (Miltefosine) treatment. Evaluations will include semen volume, sperm count, sperm concentration and motility as well as evaluation of total testosterone and FSH.
Advise women and men of the animal fertility findings, and that the potential for impaired fertility with Impavido therapy in humans has not been adequately evaluated.
Elevations of serum creatinine (Cr) were noted in clinical trials evaluating Impavido in the treatment of cutaneous, mucosal and visceral leishmaniasis. Monitor renal function weekly in patients receiving Impavido during therapy and for 4 weeks after end of therapy.
Elevations in liver transaminases (ALT, AST) and bilirubin were noted in clinical trials evaluating Impavido in the treatment of visceral leishmaniasis. Monitor liver transaminases (ALT, AST) and bilirubin during therapy in patients receiving Impavido.
In patients with clinically significant abnormality in kidney function monitoring should be continued until normalization.
Patients with severe damage of liver and kidney functions were not investigated.
Sufficient data of patients with mild and moderate impairment of liver and kidney function are not available. Patients with liver values (GOT, GPT, alkaline phosphatase) 3 times and kidney values (serum creatinine, BUN) 1.5 times above the normal range, were excluded from the clinical study.
Vomiting and diarrhea are possible side effects of a therapy with Impavido (see section 4.8). The patients must be instructed that in case of prolonged persistance of these symptoms a sufficient fluid intake must be ensured,to avoid dehydration and consequently the risk of an impaired renal function.
Thrombocytopenia during therapy has been reported in patients treated for visceral leishmaniasis. Monitor platelet count during therapy for visceral leishmaniasis
Vomiting and/or diarrhea occurring during Impavido therapy may affect the absorption of oral contraceptives, and therefore compromise their efficacy. If vomiting and/or diarrhea occur during Impavido therapy, advice females to use additional non-hormonal or alternative method(s) of effective contraception
Stevens-Johnson syndrome has been reported during Impavido therapy. Discontinue Impavido if an exfoliative or bullous rash is noted during therapy.
Data should be collected regarding QT interval in leishmaniasis patients receiving Impavido (Miltefosine) treatment to evaluate the effects of Impavido (Miltefosine) on the QT interval. ECGs and PK samples will be obtained to identify potential effects of Impavido (Miltefosine) on the QT interval or other ECG parameters.
Data should be collected regarding efficacy outcome and adverse reactions in patients with leishmaniasis who weigh more than 75kg.
In vitro investigations have shown that interactions are unlikely with medications that are metabolised by cytochrome P450 or glucuronised or conjugated otherwise. However, the possibility of interactions with commonly used medicinal products cannot entirely be excluded.
There are no adequate data from the use of miltefosine in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Impavido is contraindicated in pregnancy (see section 4.3). Women of childbearing potential have to use effective contraception during and up to 5 months aftertreatment. Vomiting and diarrhea are very common side effects of therapy with Impavido and can compromise the efficacy of oral contraception. The patient must be informed by her physician, accordingly. If necessary,suitable alternative methods of contraception must be used.
During pregnancy, visceral leishmaniasis may be life-threatening for the mother and may result in adverse fetal outcomes, including spontaneous abortion, congenital disease due to vertical transmission, small for gestational age newborn, and severe anemia. During pregnancy, cutaneous leishmaniasis may manifest with larger and atypical appearing lesions and may be associated with increased risk for adverse fetal outcomes, including preterm births and still births.
The patient has to be advised to immediately contact her physician for pregnancy testing as soon as there is any suspicion of pregnancy. If the test is positive, the physician and patient must discuss the risks associated with this pregnancy.
It is not known whether miltefosine is excreted in the milk. Impavido must not be used during lactation; Breastfeeding should be avoided for 5 months after Impavido therapy.
Studies in ratsrevealed testicular atrophies and an impairment of fertility after the treatment with miltefosine. These results were reversible after a recovery period of 10 weeks. Data with regard to the impact of miltefosine to the fertility in men are not available.
Advise women and men of the animal fertility findings, and that the potential for impaired fertility with Impavido therapy has not been adequately evaluated.
Impavido may cause undesirable effects such as nausea which may impair the patient’s ability to concentrate and react properly. In such cases patients should refrain from driving cars and using machines.
The most commonly reported adverse drug reactions are transient gastrointestinal discomfort, vomiting, diarrhea, and elevation of liver enzymes and serum creatinine. These effects are usuallymild to moderate and transient or reversible at the end of treatment and therefore do not require discontinuation oftreatment or dosage reduction. In clinicaltrials and during therapeutic use at the recommended dosagesthe following undesirable effectswere observed:
Very common (≥1/10)
Common (≥1/100 to <1/10)
Unommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to < 1/1,000)
Very rare (<1/10,000)
Very rare: Stevens-Johnson Syndrome
Very rare: Thrombocytopenia
Very common: Vomiting, diarrhea, nausea
Common: Anorexia
Unommon: Abdominal pain
Very common: Increase in liver enzymes (SGOT, SGPT, AP)
Common: Increase of BUN and creatinine
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form (http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.healt h.gov.il) or by email (adr@MOH.HEALTH.GOV.IL).
Not applicable.
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