3 de julio de 2016

Aristada: Aripiprazole lauroxil



Aripiprazole lauroxil (USAN) (brand name Aristada) is a long-acting injectable atypical antipsychotic that was developed by Alkermes. It is an N-acyloxymethyl prodrug of aripiprazole that is administered via intramuscular injection once every four to six weeks for the treatment of schizophrenia Aripiprazole lauroxil was approved by the U.S. FDA on 5 October 2015.

Aripiprazole lauroxil extended release injection (Aristada) gained FDA approval in 2015 as a treatment for adults suffering from schizophrenia. Like any long-term acting injectable, Aristada provides assurance to families and health care professionals that patients receive therapeutic medication throughout the day.

Aristada is injected into the arm or buttocks of a patient by a health care professional once every four to six weeks. Aristada is a longer-lasting and injectable version of the schizophrenia pill Abilify, which means that the treatment is available in two doses. Aristada, along with other drugs in its family, are not approved for treatment of elderly patients with dementia-related psychosis.
Schizophrenia

Aristada's approval from the Food and Drug Administration in 2015 was solely for the treatment of schizophrenia in adults. The ability to supplement Aristada with oral supplements of Abilify allows for dosing flexibility, which is important for the treatment of schizophrenia, as symptoms and intensity of the disease vary greatly from patient to patient. Additionally, as in concurrence with its sister drug Abilify, Aristada is similar in effect of typical antipsychotic drugs. In the sister drug Abilify, side effects for patients were less frequently extrapyramidal than most antipsychotic drugs.
Dosing

Aristada can be administered in three dosages of 441 mg, 662 mg and 882 mg. The smallest dosage can be injected in the Deltoid or Gluteus of the patient, while the higher doses must be injected into the Gluteus. Dosages of 441 mg or 662 mg must be repeated once every four weeks, while the dosage of 882 mg must be repeated once every six weeks.

The dosages are determined based on the daily needs of the specific patient, but the timing and injection sites are not based on the needs of the patient and correspond to the amount in each dose.
Early dosing

Aristada dosing is recommended to occur once every four weeks for doses of 441 mg or 662 mg. The recommended dosing for 882 mg is once every six weeks. These durations between doses should be maintained as much as possible. An Aristada injection should not be given any earlier than at least 14 days after the most recent injection.
Pharmacology
Mechanism of action

Arristada is injected into the intramuscles as an atypical antipsychotic. In one 12-week clinical trial involving 622 participants, the efficacy of extended aripiprazole was demonstrated.[7][10] It’s mechanism of action is unknown in the body. It is said that the drug is likely converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripirazole. The hydroxymethyl aripirazole is thus hydrolysed to aripiprazole. Aristada efficacy could be mediated through a combination of partial agonist activity D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Since Aristada is a newly approved drug by the FDA many validation of mechanisms of action are still being studied.
Pharmacodynamics

Aripiprazole exhibits high affinity for serotonin 5-HT1A, 5-HT2A receptors, dopamine D2, and dopamine D3. Moderate affinity is exhibited for serotonin 5-HT7, alpha1-adrenergic, doamine D4, histamine H1, and serotonin re-uptake site. No affinity for cholinergic muscarinic receptors have been found.
Pharmacokinetics

Aristada’s activity in the body is due to aripiprazole and also dehydro-aripiprazole. Dehydro-aripirazole has been shown to have affinities for D2 receptors. These D2 receptors have similarities to aripiprazole whereas they represent 30-40% of exposure of aripiprazole in plasma.

After 5 to 6 days of the single intramuscular injection appearance of aripiprazole in circulation, it additionally will be released for 36 days. In the fourth monthly injection, consecutive does of Aristada will reach steady-state. With additional supplements of the oral aripiprazole at a dosage of 21 days during the first dose of Aristada, aripiprazole concentrations within 4 days can reach therapeutic levels.

Important Safety Information
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ARISTADA is not approved for the treatment of patients with dementia-related psychosis.

Contraindication: Known hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis.

Cerebrovascular Adverse Reactions, Including Stroke: Increased incidence of cerebrovascular adverse reactions (eg, stroke, transient ischemic attack), including fatalities, have been reported in placebo-controlled trials of elderly patients with dementia-related psychosis treated with risperidone, aripiprazole, and olanzapine. ARISTADA is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as NMS may occur with administration of antipsychotic drugs, including ARISTADA. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available.

Tardive Dyskinesia (TD): The risk of developing TD (a syndrome of abnormal, involuntary movements) and the potential for it to become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic increase. The syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing should be consistent with the need to minimize TD. Discontinue ARISTADA if clinically appropriate. There is no known treatment for established TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include:

    Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with oral aripiprazole. Patients with diabetes should be regularly monitored for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug.
    Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
    Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Pathological Gambling and Impulse-Control Problems: Compulsive or uncontrollable urges to gamble have been reported with use of aripiprazole. Other urges less frequently reported include uncontrolled sexual urges, spending, binge eating and other impulsive and compulsive behaviors. Closely monitor patients for new or worsening uncontrollable urges. Consider dose reduction or stopping ARISTADA if a patient develops such urges.

Orthostatic Hypotension: Aripiprazole may cause orthostatic hypotension which can be associated with dizziness, lightheadedness and tachycardia. Monitor heart rate and blood pressure, and warn patients with known cardiovascular or cerebrovascular disease and risk of dehydration and syncope.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia, neutropenia, and agranulocytosis have been reported. Patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia should have frequent complete blood count (CBC) during the first few months of receiving ARISTADA. Consider discontinuation of ARISTADA at the first sign of a clinically significant decline in WBC count in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue ARISTADA in patients with severe neutropenia (absolute neutrophil count <1000 and="" follow="" mm3="" recovery.="" span="" their="" until="" wbc="">

Seizures: ARISTADA should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Potential for Cognitive and Motor Impairment: ARISTADA may impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are certain ARISTADA does not affect them adversely.

Body Temperature Regulation: Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Advise patients regarding appropriate care in avoiding overheating and dehydration. Appropriate care is advised for patients who may exercise strenuously, may be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or are subject to dehydration.

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use; use caution in patients at risk for aspiration pneumonia.

Concomitant Medication: Decreasing the ARISTADA dosage is recommended in patients taking strong CYP3A4 inhibitors and/or strong CYP2D6 inhibitors for longer than 2 weeks. Increasing the ARISTADA dosage is recommended in patients taking CYP3A4 inducers for longer than 2 weeks. No ARISTADA dosage changes are recommended for patients taking CYP450 modulators for less than 2 weeks.

Most Commonly Observed Adverse Reaction: The most common adverse reaction (≥5% incidence and at least twice the rate of placebo in patients treated with ARISTADA) was akathisia.

Injection-Site Reactions: Injection-site reactions were reported by 4%, 5%, and 2% of patients treated with 441 mg ARISTADA, 882 mg ARISTADA, and placebo, respectively. Most of these were injection-site pain and associated with the first injection and decreased with each subsequent injection. Other injection-site reactions (induration, swelling, and redness) occurred at less than 1%.

Dystonia: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first days of treatment and at low doses.

Pregnancy/Nursing: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare provider of a known or suspected pregnancy. Inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARISTADA during pregnancy. Aripiprazole is present in human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for ARISTADA and any potential adverse effects on the infant from ARISTADA or from the underlying maternal condition.
References

Rohde M, M Rk N, Håkansson AE, Jensen KG, Pedersen H, Dige T, J Rgensen EB, Holm R (2014). "Biological conversion of aripiprazole lauroxil - An N-acyloxymethyl aripiprazole prodrug". Results Pharma Sci 4: 19–25. doi:10.1016/j.rinphs.2014.04.002. PMC 4050360. PMID 25756003.
Turncliff R, Hard M, Du Y, Risinger R, Ehrich EW (2014). "Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with schizophrenia". Schizophr. Res. 159 (2-3): 404–10. doi:10.1016/j.schres.2014.09.021. PMID 25266547.
Meltzer HY, Risinger R, Nasrallah HA, Du Y, Zummo J, Corey L, Bose A, Stankovic S, Silverman BL, Ehrich EW (2015). "A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia". J Clin Psychiatry 76 (8): 1085–90. doi:10.4088/JCP.14m09741. PMID 26114240.
Citrome L (2015). "Aripiprazole Long-Acting Injectable Formulations for Schizophrenia: Aripiprazole Monohydrate and Aripiprazole Lauroxil". Expert Rev Clin Pharmacol. doi:10.1586/17512433.2016.1121809. PMID 26573020.
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