Xromi Drug Information

is indicated to reduce the frequency of painful crises and reduce the need for blood transfusions in pediatric patients aged 6 months of age and older with sickle cell anemia with recurrent moderate to severe painful crises. XROMI is an antimetabolite indicated to reduce the frequency of painful crises and reduce the need for blood transfusions in pediatric patients aged 6 months of age and older with sickle cell anemia with recurrent moderate to severe painful crises.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of XROMI was evaluated in 32 pediatric patients aged 10 months -16 years with sickle cell anemia in a single-arm, open-label, prospective, multi-center, pharmacokinetic, safety and efficacy study (HUPK study). Only adverse reactions associated with the use of XROMI in pediatric patients aged 10 months to less than 2 years are presented. The most frequently reported adverse reactions in HUPK study (<33%) were neutropenia, and thrombocytopenia.

Table 3. Adverse Reactions Reported in Pediatric Patients Aged 10 Months and Older Enrolled in HUPK 10 Months–<2 Years 2 –<6 Years 6 –<18 Years Overall Body System Adverse Reactions (n=6)% (n=16)% (n=10)% (n=32)% Neutropenia 3 1 0 4 Thrombocytopenia 2 1 0 3 Diarrhea 1 0 0 1 GGT Increased 0 0 1 1 Absolute Reticulocyte Count Decreased 1 0 0 1 Alopecia 0 1 0 1 Nail Discolouration 0 0 1 1 Rash 0 0 1 1 Rash Popular 0 1 1 2

Post marketing Experience

The following adverse reactions have been identified during post-approval use of hydroxyurea. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency. Reproductive System and Breast disorders: azoospermia, and oligospermia Gastrointestinal disorders: stomatitis, nausea, vomiting, diarrhea, and constipation Metabolism and Nutrition disorders: anorexia Skin and subcutaneous tissue disorders: maculopapular rash, skin ulceration, cutaneous lupus erythematosus, dermatomyositis-like skin changes, peripheral and facial erythema, hyperpigmentation, nail hyperpigmentation, atrophy of skin and nails, scaling, violet papules, and alopecia Renal and urinary disorders: dysuria, elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels Nervous system disorders: headache, dizziness, drowsiness, disorientation, hallucinations, and convulsions General disorders: fever, chills, malaise, edema, and asthenia Hepatobiliary disorders: elevation of hepatic enzymes, cholestasis, and hepatitis Respiratory disorders: diffuse pulmonary infiltrates, dyspnea, and pulmonary fibrosis, interstitial lung disease, pneumonitis, alveolitis, allergic alveolitis and cough Immune disorders: systemic lupus erythematosus Hypersensitivity: Drug-induced fever (pyrexia) (>39°C, >102°F) requiring hospitalization has been reported concurrently with gastrointestinal, pulmonary, musculoskeletal, hepatobiliary, dermatological or cardiovascular manifestations.

Onset typically occurred within 6 weeks of initiation and resolved upon discontinuation of hydroxyurea. Upon re-administration fever reoccurred typically within 24 hours. Blood and lymphatic system disorders: hemolytic anemia

Increased Toxicity with

Concomitant Use of Antiretroviral Drugs Pancreatitis In patients with HIV infection during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal cases of pancreatitis have occurred. Hydroxyurea is not indicated for the treatment of HIV infection; however, if patients with HIV infection are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis is recommended. Permanently discontinue therapy with hydroxyurea in patients who develop signs and symptoms of pancreatitis.

Hepatotoxicity Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with HIV infection treated with hydroxyurea and other antiretroviral drugs. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. Avoid this combination.

Peripheral Neuropathy Peripheral neuropathy, which was severe in some cases, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral drugs, including didanosine, with or without stavudine.

Laboratory Test Interference Interference with Uric Acid, Urea, or Lactic Acid Assays

Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with hydroxyurea. Interference with Continuous Glucose Monitoring Systems Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may lead to hypoglycemia if sensor glucose results are relied upon to dose insulin. If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods.

Pregnancy Risk Summary XROMI can cause fetal harm based on findings from animal studies and the drug’s mechanism of action. There are no data with XROMI use in pregnant women to inform a drug-associated risk. In animal reproduction studies, administration of hydroxyurea to pregnant rats and rabbits during organogenesis produced embryotoxic and teratogenic effects at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m 2 basis (see Data ). Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated with XROMI. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

Data Animal Data Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m 2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m 2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m 2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays.

Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m 2 basis) to rats caused growth retardation and impaired learning ability.

Pediatric Use The safety and effectiveness of XROMI have been established in pediatric patients aged 6 months and older with sickle cell anemia with recurrent moderate to severe painful crises. Use of XROMI in these age groups is supported by evidence from a pharmacokinetic, efficacy and safety study, in which 32 pediatric patients ages 6 months to <18 years were enrolled. Among the 32 pediatric patients treated with XROMI, 6 were infants (6 months – 2 years), 16 children (2-6 years) and 10 were adolescents (6-18 years). Continuous follow-up of the growth of treated children is recommended.

is contraindicated in patients: who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. . In patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation.

Acute mucocutaneous toxicity and neutropenia has been reported in patients receiving hydroxyurea at doses several times above the therapeutic dose. Soreness, violet erythema, oedema on palms and soles followed by scaling of hand and feet, severe generalized hyperpigmentation of the skin and stomatitis have been observed.