İHALE DÜNYASI
İHALE DÜNYASI
OLPRUVA (sodium phenylbutyrate) for oral suspension is a nitrogen binding agent. Sodium phenylbutyrate is a white to yellowish-white powder. It is freely soluble in water and in methanol, and practically insoluble in acetone and diethyl ether. It is known chemically as sodium 4-phenylbutyrate with a molecular weight of 186.19 and molecular formula C 10 H 11 NaO 2 . Structural Formula: OLPRUVA is supplied in dosage envelopes containing 2 g (equivalent to 1.75 g phenylbutyrate), 3 g (equivalent to 2.63 g phenylbutyrate), 4 g (equivalent to 3.51 g phenylbutyrate), 5 g (equivalent to 4.38 g phenylbutyrate), 6 g (equivalent to 5.26 g phenylbutyrate), and 6.67 g (equivalent to 5.85 g phenylbutyrate) of sodium phenylbutyrate in one or two packets. OLPRUVA is a polymer coated formulation which contains the following inactive ingredients: amino methacrylate copolymer, hypromellose, microcrystalline cellulose, polyethylene glycol 6000, silicon dioxide, and talc. Structural Formula
OLPRUVA is indicated as adjunctive therapy to standard of care, which includes dietary management, for the chronic management of adult and pediatric patients weighing 20 kg or greater and with a body surface area (BSA) of 1.2 m 2 or greater, with urea cycle disorders (UCDs) involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS). OLPRUVA is a nitrogen-binding agent indicated as adjunctive therapy to standard of care, which includes dietary management, for the chronic management of adult and pediatric patients weighing 20 kg or greater and with a body surface area (BSA) of 1.2 m 2 or greater, with urea cycle disorders (UCDs) involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS). ( 1 ) Limitations of Use: OLPRUVA is not indicated for the treatment of acute hyperammonemia. ( 1 ) Limitations of Use Episodes of acute hyperammonemia may occur in patients while on OLPRUVA. OLPRUVA is not indicated for the treatment of acute hyperammonemia, which can be a life-threatening medical emergency that requires rapid acting interventions to reduce plasma ammonia levels.
OLPRUVA treatment should be supervised by a healthcare provider experienced in the treatment of UCDs. For preparation and administration, see full prescribing information. ( 2.1 , 2.4 ) The recommended dosage is 9.9 -13 g/m 2 /day. ( 2.1 ) Monitor plasma ammonia levels to determine the need for dosage adjustment. ( 2.2 ) Monitor patients for potential neurotoxicity. ( 2.2 ) For patients with hepatic impairment, start at the lower end of the recommended dosing range. ( 2.3 ) 2.1 Recommended Dosage OLPRUVA treatment should be supervised by a healthcare provider experienced in the treatment of urea cycle disorders. The recommended dosage of OLPRUVA for patients with urea cycle disorders is 9.9 -13 g/m 2 /day orally. Divide the calculated total daily dose into three to six doses. Administer as three to six divided doses and take with food. Round each individual dose of OLPRUVA to the nearest available dosage strength. The maximum dosage is 20 grams per day. Combine OLPRUVA with dietary protein restriction and, in some cases, amino acid supplementation (e.g., essential amino acids, arginine, citrulline, and protein-free calorie supplements). If a dose is missed, take the missed dose as soon as possible on the same day. 2.2 Dosage Administration and Monitoring Monitor plasma ammonia levels to determine the need for dosage adjustment. Adjust the OLPRUVA dosage to maintain the plasma ammonia level within the normal range for the patient's age, taking into consideration their clinical condition (e.g., nutritional requirements, protein intake, growth parameters, etc.). Monitor patients for potential neurotoxicity and obtain measurements of plasma phenylacetate and phenylacetylglutamine levels [ see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6 ) ]. If neurologic symptoms (e.g., vomiting, nausea, headache, somnolence, or confusion) are present in the absence of high ammonia levels or other incurrent illnesses, consider reducing the dose of OLPRUVA. 2.3 Dosage Adjustment in Patients with Hepatic Impairment For patients with hepatic impairment, start at the lower end of the recommended dosing range and maintain patients on the lowest dose necessary to control plasma ammonia levels [ see Use in Specific Populations ( 8.7 ) ]. 2.4 Preparation and Administration Instructions For oral administration only. Do not administer via gastrostomy or nasogastric tubes. Pour the entire contents of the Mix-Aid packet into approximately 4 ounces of water in a cup and stir, forming a suspension. Pour the entire contents of the OLPRUVA packet(s) into the suspension and stir. Drink the entire suspension within 5 minutes after stirring to minimize dissolution of coating. After 30 minutes, the suspension should be discarded. Pour another 4 ounces of water into the cup and drink to make sure that any OLPRUVA remaining in the cup is consumed.
None. None. ( 4 )
The following adverse reactions associated with the use of sodium phenylbutyrate were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Most common adverse reactions (incidence ? 3%) are amenorrhea or menstrual dysfunction (irregular menstrual cycles), decreased appetite, body odor and bad taste or taste aversion. Less Common Clinical Adverse Reactions Blood and lymphatic system disorders: aplastic anemia, ecchymoses Cardiac disorders: arrhythmia Gastrointestinal disorders: abdominal pain, gastritis, nausea and vomiting, constipation, rectal bleeding, peptic ulcer disease, pancreatitis Metabolism and nutrition disorders: increased weight, edema Nervous system disorders: syncope, headache Psychiatric disorders: depression Renal and urinary disorders: renal tubular acidosis Skin and subcutaneous tissue disorders: rash Laboratory Adverse Reactions Blood and lymphatic system disorders: anemia, leukopenia and leukocytosis, thrombocytopenia, thrombocytosis Hepatobiliary disorders: hyperbilirubinemia, increased blood alkaline phosphatase, increased transaminases Metabolism and nutrition disorders: acidosis, alkalosis, hyperchloremia, hypophosphatemia, hyperuricemia, hyperphosphatemia, hypernatremia, hypokalemia, hypoalbuminemia, decreased total protein Clinical Adverse Reactions with Use of Phenylacetate Nervous system disorders: Neurotoxicity was reported in cancer patients receiving intravenous phenylacetate, the major metabolite of OLPRUVA (OLPRUVA is not approved for intravenous use or for treatment of patients with cancer). Signs and symptoms were predominately somnolence, fatigue, and dizziness (lightheadedness); less frequently reported were headache, dysgeusia, hypoacusis, disorientation, memory impairment, and exacerbation of a pre-existing neuropathy. Most common adverse reactions (incidence ? 3%) are menstrual dysfunction, decreased appetite, body odor and bad taste or taste aversion. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Acer Therapeutics Inc. at 1-844-600-2237 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Neurotoxicity of Phenylacetate : Increased exposure to phenylacetate, the major metabolite of OLPRUVA, may be associated with neurotoxicity in patients with UCDs. Consider reducing the dose if neurotoxicity symptoms are present. ( 5.1 ) Hypokalemia : Renal excretion of phenylacetylglutamine may induce urinary loss of potassium. Monitor serum potassium during therapy and initiate appropriate treatment when necessary. ( 5.2 ) Conditions Associated with Edema : Calculate the total amount of sodium patients will be exposed to based on their body surface area. If a patient develops new-onset edema or worsening edema while on treatment, discontinue administration of OLPRUVA and initiate appropriate therapy. ( 5.3 ) 5.1 Neurotoxicity of Phenylacetate Increased exposure to phenylacetate, the major metabolite of OLPRUVA, may be associated with neurotoxicity in patients with UCDs. In a study of adult cancer patients receiving intravenous phenylacetate, 250-300 mg/kg/day for 14 days, repeated at 4-week intervals, signs and symptoms of neurotoxicity, which were reversible upon discontinuation, were seen at plasma concentrations ? 3.5 mmol/L, and included somnolence, fatigue, and light headedness [ see Adverse Reactions ( 6 ) ]. OLPRUVA is not approved for intravenous use or for treatment of patients with cancer. If symptoms of vomiting, nausea, headache, somnolence, or confusion are present in the absence of high ammonia levels or other intercurrent illnesses, consider reducing the dose of OLPRUVA [ see Dosage and Administration ( 2.2 ) ]. Phenylacetate caused neurotoxicity when given subcutaneously in rat pups [ see Use in Specific Populations ( 8.4 ) ]. 5.2 Hypokalemia Renal excretion of phenylacetylglutamine may induce urinary loss of potassium. Monitor serum potassium during therapy and initiate appropriate treatment when necessary. 5.3 Conditions Associated with Edema OLPRUVA contains 124 mg (5.4 mmol) of sodium per gram of sodium phenylbutyrate (12.4% w/w) and the Mix-Aid contains 5 mg of sodium per packet, corresponding to 2.5 g (108 mmol) of sodium in the maximum daily dose of 20 g of OLPRUVA. In order to decide if administration of OLPRUVA is appropriate in patients with diseases that involve edema, such as heart failure, cirrhosis, or nephrosis, calculate the total amount of sodium patients will be exposed to based on their BSAs [ see Dosage and Administration ( 2.1 ) ]. If a patient develops new-onset edema or worsening edema while on treatment, discontinue administration of OLPRUVA and initiate appropriate therapy.
Valproic Acid, Haloperidol, or Corticosteroids : May increase plasma ammonia levels; monitor ammonia levels closely. ( 7.1 ) Probenecid : May inhibit renal excretion of metabolites of OLPRUVA including phenylacetate and phenylacetylglutamine; monitor for potential neurotoxicity. ( 7.2 ) 7.1 Potential for Other Drugs to Affect Ammonia Corticosteroids Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels. Valproic Acid and Haloperidol Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor plasma ammonia levels closely when corticosteroids, valproic acid, or haloperidol is used concomitantly with OLPRUVA. 7.2 Potential for Other Drugs to Affect OLPRUVA Probenecid Probenecid may inhibit renal excretion of the metabolites of OLPRUVA including phenylacetate and phenylacetylglutamine. Monitor patients for potential neurotoxicity and measure plasma phenylacetate and phenylacetylglutamine levels when probenecid is used concomitantly with OLPRUVA [ see Dosage and Administration ( 2.2 ) ].