Lybalvi
Lybalvi Uses, Dosage, Side Effects, Food Interaction and all others data.
Olanzapine is an antipsychotic agent and has affinities for serotonin 5HT2A/2C, 5HT3, 5HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α1 adrenergic; and histamine H1 receptors. The mechanism of action of Olanzapine, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug’s efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism.
Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. Olanzapine is not mutagenic or clastogenic as well as not carcinogenic.
The effect of olanzapine in the D2 receptor is reported to produce the positive effects of this drug such as a decrease in hallucinations, delusions, disorganized speech, disorganized thought, and disorganized behavior. On the other hand, its effect on the serotonin 5HT2A receptor prevents the onset of anhedonia, flat affect, alogia, avolition and poor attention. Based on the specific mechanism of action, olanzapine presents a higher affinity for the dopamine D2 receptor when compared to the rest of the dopamine receptor isotypes. This characteristic significantly reduces the presence of side effects.
Clinical trials for the original use of olanzapine demonstrated significant effectiveness in the treatment of schizophrenia and bipolar disorder in adults and acute manic or mixed episodes associated with bipolar disorder in adolescents.
The effect of olanzapine on dopamine and serotonin receptors has been suggested to reduce chemotherapy-induced nausea and vomiting as those receptors are suggested to be involved in this process. For this effect, several clinical trials have been conducted and it has been shown that olanzapine can produce a significant increase in total control of nausea and vomiting. In a high-level study of the effect of olanzapine for this condition, a complete response on the delay phase was observed in 84% of the individual and control of emesis of over 80% despite the phase.
Olanzapine is an effective atypical antipsychotic that, like other antipsychotics, is associated with weight gain, metabolic dysfunction, and increased risk of type II diabetes. Samidorphan is a novel opioid antagonist structurally related to naltrexone, with a higher affinity for opioid receptors, more potent μ-opioid receptor antagonism, higher oral bioavailability, and a longer half-life, making it an attractive candidate for oral dosing. Although antipsychotic-induced weight gain is incompletely understood, it is thought that the opioid system plays a key role in feeding and metabolism, such that opioid antagonism may be expected to ameliorate these negative effects. Samidorphan has been shown in animal models and clinical trials to ameliorate olanzapine-induced weight gain and metabolic dysfunction.
Samidorphan was first approved as a variety of fixed-dose combination tablets with olanzapine by the FDA on May 28, 2021, and is currently marketed under the trademark LYBALVI™ by Alkermes Inc.
Samidorphan, a novel opioid-system modulator, functions primarily as a μ-opioid receptor antagonist and as a κ/δ-opioid receptor partial agonist in vitro with an overall profile consistent with a μ-opioid receptor antagonist in vivo and is currently used to counteract olanzapine-induced adverse effects of weight gain and metabolic dysfunction. Samidorphin generally has a mild side effect profile. As an opioid antagonist, it can potentiate opioid withdrawal in dependent patients; it should not be administered within seven days from the last use of short-acting opioids and at least 14 days after cessation of long-acting opioids. Similarly, samidorphan use may lead to life-threatening opioid overdose, either in patients who attempt to overcome the samidorphan-induced opioid blockade or resume opioid use when therapy is interrupted or discontinued.
| Trade Name | Lybalvi |
| Generic | Olanzapine + samidorphan |
| Type | Tablets |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Olanzapine is used for the acute and maintenance treatment of schizophrenia and related psychoses where positive symptoms (e.g. delusions, hallucinations, disordered thinking, hostility and suspiciousness) and/or negative symptoms (e.g. flattened affect, emotional and social withdrawal, poverty of speech) are prominent.
Olanzapine is used for the treatment of acute manic or mixed episodes in bipolar disorder, with or without psychotic features and with or without a rapid cycling course
Samidorphan is a novel opioid-system modulator, similar to naltrexone, that functions primarily as a μ-opioid receptor antagonist in vivo and is used primarily in combination with antipsychotics to reduce their metabolic dysfunction-associated adverse effects.
Samidorphan is indicated in combination with olanzapine for the treatment of bipolar I disorder, either as an adjunct to lithium or valproate or as monotherapy for the acute treatment of manic or mixed episodes or as maintenance therapy, and for the treatment of schizophrenia in adults.
Lybalvi is also used to associated treatment for these conditions: Acute Agitation, Acute Depressive Episode, Bipolar 1 Disorder, Bipolar Disorder With Manic or Mixed Episodes, Delirium, Delusional Parasitosis, Gilles de la Tourette's Syndrome, Major depressive disorder, recurrent episode, Mixed manic depressive episode, Post Traumatic Stress Disorder (PTSD), Psychosis, Schizophrenia, Acute Manic episodeBipolar 1 Disorder, Bipolar Disorder With Manic or Mixed Episodes, Schizophrenia
How Lybalvi works
The activity of olanzapine is achieved by the antagonism of multiple neuronal receptors including the dopamine receptor D1, D2, D3 and D4 in the brain, the serotonin receptors 5HT2A, 5HT2C, 5HT3 and 5HT6, the alpha-1 adrenergic receptor, the histamine receptor H1 and multiple muscarinic receptors.
As abovementioned, olanzapine presents a wide profile of targets, however, its antagonistic effect towards the dopamine D2 receptor in the mesolimbic pathway is key as it blocks dopamine from having a potential action at the post-synaptic receptor. The binding of olanzapine to the dopamine D2 receptors is easily dissociable and hence, it allows for a certain degree of dopamine neurotransmission.
On the other hand, olanzapine acts in the serotonin 5HT2A receptors in the frontal cortex in a similar manner than the reported on dopamine D2 receptors. This determined effect allows for a decrease in adverse effects.
Samidorphan is a novel naltrexone analogue containing a 3-carboxamido group that functions as an opioid receptor modulator, both in vitro and in vivo. Numerous in vitro studies have demonstrated that samidorphan binds with high affinity to the μ-, κ-, and δ-opioid receptors with Ki values of 0.052 ± 0.0044, 0.23 ± 0.018, and 2.7 ± 0.36 nM, respectively. Samidorphan acts as an antagonist at the μ-opioid receptor when it signals through Gαi proteins, a partial agonist when the receptor signals through GαoA, GαoB, and Gαz proteins, and essentially lacks β-arrestin-mediated signalling; samidorphan also acts as a partial agonist at both the κ- and δ-opioid receptors in vitro. In addition, both the major N-dealkylated and the major N-oxide human metabolites bind to the μ-, κ-, and δ-opioid receptors (Ki values of 0.26, 23, and 56, and 8, 110, and 280 nM, respectively); the former functions as a μ-opioid receptor agonist and the latter as an antagonist. Overall, samidorphan functions primarily as a μ-opioid antagonist in vivo.
Olanzapine is an efficacious antipsychotic whose use is limited, in part, by known adverse effects mediated through metabolic dysfunction: hyperglycemia/diabetes mellitus, hyperlipidemia, and weight gain. The exact mechanisms behind this metabolic dysfunction are incompletely understood, but it is known that opioid signalling is involved in feeding and metabolism. Clinical studies have demonstrated that the addition of samidorphan to olanzapine helps mitigate its metabolic-related adverse effects; presumably, this is due to opioid receptor signalling, though the exact mechanism remains to be determined. The appropriateness of samidorphan in combination therapy is due in part to its relatively mild side effect profile and low abuse potential.
Dosage
Lybalvi dosage
The recommended starting dose for Olanzapineis 10 mg/day, administered as a single daily dose without regard to meals. Daily dosage may subsequently be adjusted on the basis of individual clinical status within the range of 5-20 mg daily. An increase to a dose greater than the routine therapeutic dose of 10 mg/day i.e. to a dose of 15 mg/day or greater, is recommended only after appropriate clinical reassessment.
Children: Olanzapine has not been studied in subjects under 18 years of age.
Elderly patients (age 65 and over): starting dose 5 mg/day
Patients with hepatic and/or renal impairment: starting dose 5 mg/day
When more than one factor is present which might result in slowermetabolism (female gender, geriatric age, non-smoking status), consideration should be given to decreasing the starting dose. Dose escalation, when indicated, should be conservative in such patients.
Side Effects
Very common undesirable effects are somnolence and weight gain. Besides increased appetite, elevated glucose levels, elevated triglyceride levels, dizziness, akathisia, Parkinson's disease, dyskinesia, orthostatic hypotension, mild and transient anticholinergic effects including constipation and dry mouth, asthenia, edema and photosensitivity reaction etc. may be observed.
Toxicity
The toxicity symptoms of olanzapine are known to include somnolence, mydriasis, blurred vision, respiratory depression, hypotension, extrapyramidal symptoms and anticholinergic effects. The overdosage effects in children are generally associated with more significant side effects.
The maximum registered dosage of olanzapine in clinical trials was of 300 mg and it was reported to present drowsiness and slurred speech. However, on post-marketing surveillance, a wide range of symptoms have been presented including agitation, dysarthria, tachycardia, extrapyramidal symptoms, and reduced consciousness. One case of overdosage-driven death was reported after ingestion of 450 mg of olanzapine. In the cases of acute overdosage, the establishment of adequate oxygenation and ventilation, gastric lavage and administration of activated charcoal with a laxative is recommended.
In carcinogenesis studies, olanzapine was showed to present an increase in the incidence of liver hemangiomas and hemangiosarcomas as well as mammary gland adenomas, and adenocarcinomas. On fertility studies, there was solely found impairment in male mating performance and delays in ovulation. There is no evidence of mutagenic, genotoxic potential not adverse events on fertility.
There is limited information regarding samidorphan overdose. During clinical trials for the combination of olanzapine and samidorphan, overdose was recognized in 7/861 patients, none of which were fatal. One patient who ingested 5.5- and 11-times the maximum daily dosage of olanzapine and samidorphan, respectively, was unresponsive and admitted to the hospital but stabilized within two days. As there are no known antidotes for overdose with this combination, symptomatic and supportive measures are recommended.
Precaution
Olanzapine should be used cautiously in patients who have a history of seizures or have conditions associated with seizures. Olanzapine should be used cautiously in patients with low leukocyte and/or neutrophil counts for any reason, drug induced bone marrow depression/toxicity caused by radiation therapy or chemotherapy, hypereosinophilic conditions, impaired hepatic function, and patients using hepatotoxic medicines, centrally acting drug and medicines know to increase QT interval, especially in the elderly. Patients should be cautioned about operating hazardous machinery, including motor vehicles.
Interaction
Drugs that induce CYP1A2 or glucoronyl transferase enzymes (omeprazole, rifampicin), inhibitor of CYP1A2 (fluvoxamine), centrally acting drugs, antihypertensive agents.
Volume of Distribution
The volume of distribution of olanzapine is reported to be of 1000 liters which indicate a large distribution throughout the body.
Samidorphan following a single 10 mg oral dose had an apparent volume of distribution between 336.59 ± 75.42 and 557.6 ± 120.51 L, depending on age, gender, and concomitant food consumption.
Elimination Route
Olanzapine presents a linear pharmacokinetic profile and, after daily administration, it reaches steady-state in about a week. Under the administration of a normal dosage of olanzapine, the steady-state plasma concentration does not seem to exceed 150 ng/ml with an AUC of 333 ng/h/ml.
The absorption of olanzapine is not affected by the concomitant administration of food. The pharmacokinetic profile of olanzapine is characterized by reaching peak plasma concentration of 156.9 ng/ml approximately 6 hours after oral administration.
Samidorphan pharmacokinetics are linear over the range of clinically relevant concentrations, and steady-state kinetics are reached by seven days with once-daily oral administration. Upon reaching steady-state, with a once-daily dose of 10 mg samidorphan combined with 20 mg olanzapine, samidorphan has a mean Cmax of 45.1 ± 11.4 ng/mL and an AUC24h of 364 ± 112 ng*h/mL. Samidorphan has an absolute oral bioavailability of 69% and a Tmax of 1-2 hours.
Samidorphan pharmacokinetics are not significantly impacted by food; following a high-fat meal, the Cmax was 0.85 (90% CI 0.76, 0.94) and the AUC 1.03 (90% CI 1.0, 1.05) that for the fasted state.
Half Life
Olanzapine presents a half-life ranging between 21 to 54 hours with an average half-life of 30 hours.
Samidorphan has a mean half-life of 7-11 hours.
Clearance
The mean clearance rate of olanzapine is of 29.4 L/hour however, some studies have reported an apparent clearance of 25 L/h.
Samidorphan has a mean clearance of 35-45 L/h.
Elimination Route
Olanzapine is mainly eliminated through metabolism and hence, only 7% of the eliminated drug can be found as the unchanged form. It is mainly excreted in the urine which represents around 53% of the excreted dose followed by the feces that represent about 30%.
Samidorphan is primarily renally excreted, with 67% of unchanged parent and metabolites eliminated in urine and another 16% in feces.
Pregnancy & Breastfeeding use
Olanzapine should be used in pregnancy only if the potential benefits justify the potential risk to the foetus. So, patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with Olanzapine. There is no report to show teratogenecity. Patients should not breast feed if they are taking Olanzapine.
Contraindication
This is contraindicated in those patients with a known hypersensitivity to Olanzapine as well as in patients with known risk for narrow-angle glaucoma.
Concomitant illness: Olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.
Neuroleptic Malignant Syndrome (NMS): If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.
Acute Overdose
Symptoms: Tachycardia, agitation/aggressiveness, dysarthria, extrapyramidal symptoms, reduced level of consciousness ranging from sedation to coma.
Management: Symptomatic and supportive treatment. Gastric lavage and admin of activated charcoal may be effective.
Storage Condition
Store below 30˚ C. Protect from light and moisture. Keep out of the reach of children.
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