DRUG INTERACTIONS

Methadone: Methadone and LUCEMYRA both prolong the QT interval. ECG monitoring is recommended when used concomitantly.

 Oral Naltrexone: Comcomitant use may reduce efficacy of oral naltrexone. 

CYP2D6 Inhibitors: Concomitant use of paroxetine resulted in increased plasma levels of LUCEMYRA. Monitor for symptoms of orthostasis and bradycardia with concomitant use of a CYP2D6 inhibitor.

SHORT SUMMARY

10/18. Lofexidine hydrochloride -(MAY 2018)

Indn-     For the non-opiod treatment for management of  opioid withdrawal symptoms in adults 

Comp-   Tablets: 0.18 mg. The usual dosage is three 0.18 mg tablets taken orally 4 times daily at 5- to 6-hour intervals treatment may be continued for up to14 days with dosing guided by symptoms.

ADR-   Most common adverse reactions (incidence = 10% and notably more frequent than placebo) are orthostatic hypotension, bradycardia, hypotension, dizziness, somnolence, sedation, and dry mouth. 

CI-   None

Pat Inform-                                                                                                                 

 may mitigate, but not completely prevent, the symptoms associated with opioid withdrawal syndrome, which may include feeling sick, stomach cramps, muscle spasms or twitching, feeling of cold, heart pounding, muscular tension, aches and pains, yawning, runny eyes and sleep problems (insomnia).

Patients should be advised that withdrawal will not be easy. Additional supportive measures should be clearly advised, as needed.

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  10

 ADVERSE REACTIONS 

Most common adverse reactions (incidence = 10% and notably more frequent than placebo) are orthostatic hypotension, bradycardia, hypotension, dizziness, somnolence, sedation, and dry mouth. 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

LUCEMYRA may mitigate, but not completely prevent, the symptoms associated with opioid withdrawal syndrome, which may include feeling sick, stomach cramps, muscle spasms or twitching, feeling of cold, heart pounding, muscular tension, aches and pains, yawning, runny eyes and sleep problems (insomnia).

Patients should be advised that withdrawal will not be easy. Additional supportive measures should be clearly advised, as needed.

Hypotension and Bradycardia-                                                                                Inform patients to be alert for any symptoms of low blood pressure or pulse (e.g., dizziness, lightheadedness, or feelings of faintness at rest or on abruptly standing).

Advise patients on how to reduce the risk of serious consequences should hypotension occur (sit or lie down, carefully rise from a sitting or lying position).

Patients being given LUCEMYRA in an outpatient setting should be capable of and instructed on self-monitoring for hypotension, orthostasis and bradycardia and advised to withhold LUCEMYRA doses and contact their healthcare provider for instructions if they experience these signs or related symptoms

Advise patients to avoid becoming dehydrated or overheated, which may potentially increase the risks of hypotension and syncope

Concomitant Medications Review with the patient all concomitant medications being taken and request that the patient immediately inform their healthcare provider of any changes in concomitant medications, including any other medications that may be used to treat individual symptoms of withdrawal.

Increased Risk of CNS Depression with Concomitant use of CNS Depressant Drugs-                                                                                                                         Inform patients of the increased risk of CNS depression with concomitant use of benzodiazepines, alcohol, barbiturates, or other sedating drugs

 Advise patients using LUCEMYRA in an outpatient setting that, until they learn how they respond to LUCEMYRA, they should be careful or avoid doing activities such as driving or operating heavy machinery.

 Sudden Discontinuation of LUCEMYRA                                                                Inform patients not to discontinue LUCEMYRA without consulting their healthcare provider 

 Risk of Opioid Overdose-                                                                                             After Discontinuation of Opioids Advise patients that after a period of not using opioid drugs, they may be more sensitive to the effects of opioids and at greater risk of overdosing [see Warnings and Precautions (5.4)]. Reference ID: 4263583

Distributed by:

US WorldMeds, LLC 4441 Springdale Road Louisville, KY 40241 Under License from Britannia Pharmaceuticals Limited. US WorldMeds, LLC is the exclusive licensee and distributor of LUCEMYRA™ 

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                      Lofexidine is a central alpha-2 adrenergic agonist that binds to receptors on adrenergic neurons. This reduces the release of norepinephrine and decreases sympathetic tone.

2. Pharmacodynamics-                                                                                               s of  Patients with hepatic impairment- Administration of LUCEMYRA to subjects with hepatic impairment was associated with prolongation of the QTc interval, which was more pronounced in subjects with severe hepatic impairmen

Administration of LUCEMYRA to subjects with renal impairment was associated with prolongation of the QTc interval, which was more pronounced in subjects with severe renal impairment

3. Pharmacokinetics                                                                                           Absorption                                                                                                             LUCEMYRA is well absorbed and achieves peak plasma concentration 3 to 5 hours after administration of a single dose. LUCEMYRA shows approximately dose pioportional pharmacokinetics.

Administration of LUCEMYRA with food does not alter its pharmacokinetics.

The absolute bioavailability of a single oral LUCEMYRA dose ( 0.36 mg in solution ) compared with an intravenous infusion (0.2 mg infused for 200 minutes) was 72%.   Mean LUCEMYRA Cmax after the oral dose and intravenous infusion was 0.82 ng/mL (at median Tmax of 3 hours) and 0.64 ng/mL (at median Tmax of 4 hours), respectively. Mean estimates of overall systemic exposure (AUCinf) were 14.9 ng•h/mL and 12.0 ng•h/mL, respectively. 

Distribution-                                                                                                                Mean LUCEMYRA apparent volume of distribution and volume of distribution values following the administration of an oral dose and an intravenous dose were 480.0 L and 297.9 L, respectively, which are appreciably greater than total body volume, suggesting extensive LUCEMYRA distribution into body tissue. LUCEMYRA protein binding is approximately 55%. LUCEMYRA is not preferentially taken up by blood cells.

 Metabolism-                                                                                                                From absolute bioavailability results, approximately 30% of the administered LUCEMYRA dose is converted to inactive metabolites during the first pass effect associated with drug absorption from the gut. 

 LUCEMYRA and its major metabolites did not induce or inhibit any CYP450 isoforms, with the exception of a slight inhibition of CYP2D6 by LUCEMYRA, with an IC50 of 4551 nM (approximately 225 times the steady-state Cmax for LUCEMYRA with 0.72 mg 4 times daily dosing).

Elimination-                                                                                                                    The elimination half-life is approximately 12 hours and mean clearance is 17.6 L/h following an IV infusion. LUCEMYRA has a terminal half-life of approximately 11 to 13 hours following the first dose. At steady-state, the terminal half-life is approximately 17 to 22 hours.

Accumulation occurs up to 4 days with repeat dosing, following the recommended dosing regimen.

Renal elimination of unchanged drug accounts for approximately 15% to 20% of the administered dose. 

Hepatic Impairment-                                                                                                Hepatic impairment slows the elimination of LUCEMYRA but exhibits less effect on the peak plasma concentration following a single dose.

In Subjects with Hepatic Impairment Normal Mild Impairment Moderate Impairment Severe Impairment Child-Pugh Class & Score Normal Function Class A 5-6 Class B 7-9 Class C 10-15 Cmax % of normal 100 114 117 166 AUClast % of normal 100 127 190 304 AUC8 % of normal 100 117 185 260 t1/2 % of normal 100 139 281 401

Renal Impairment-                                                                                                      Renal impairment slows the elimination of LUCEMYRA but exhibits less effect on the peak plasma concentration following a single dose.

 USE IN SPECIFIC POPULATIONS

1.Pregnancy Risk Summary

The safety of LUCEMYRA in pregnant women has not been established.

In animal reproduction studies, oral administration of lofexidine during organogenesis to pregnant rats and rabbits caused a reduction in fetal weights, increases in fetal resorptions, and litter loss at exposures below that in humans.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies carry some risk of birth defect, loss, or other adverse outcomes.

The background risk of major birth defects in the U.S. general population is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

2. Lactation Risk Summary-                                                                                         There is no information regarding the presence of LUCEMYRA or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Caution should be exercised when LUCEMYRA is administered to a nursing woman.

The developmental and health benefits should be considered along with the mother’s clinical need for LUCEMYRA and any other potential adverse effects on breast-fed children from LUCEMYRA or from the underlying maternal condition.

3. Females and Males of ReproductivePotential-                                                               In animal studies that included some fertility endpoints, lofexidine decreased breeding rate and increased resorptions at exposures below human exposures. The impact of lofexidine on male fertility has not be adequately characterized in animal studies 

4. Pediatric Use-                                                                                                            The safety and effectiveness of LUCEMYRA have not been established in pediatric patients. 

5. Geriatric Use-                                                                                                              No studies have been performed to characterize the pharmacokinetics of LUCEMYRA or establish its safety and effectiveness in geriatric patients.                                   

Caution should be exercised when it is administered to patients over 65 years of age. Dosing adjustments similar to those recommended in patients with renal impairment should be considered

6.Hepatic Impairment-                                                                                             Hepatic impairment slows the elimination of LUCEMYRA but exhibits less effect on the peak plasma concentration than on AUC values following a single dose. Dosage adjustments are recommended based on the degree of hepatic impairment.         Clinically relevant QT prolongation may occur in subjects with hepatic impairment.

7. Renal Impairment-                                                                                                  Renal impairment slows the elimination of LUCEMYRA but exhibits less effect on the peak plasma concentration than on AUC values following a single dose. Dosage adjustments are recommended based on the degree of renal impairment.

Only a negligible fraction of the LUCEMYRA dose is removed during a typical dialysis session, so no additional dose needs to be administered after a dialysis session; LUCEMYRA may be administered without regard to the timing of dialysis DosagesClinically relevant QT prolongation may occur in subjects with renal impairment.

8.CYP2D6 Poor Metabolizers-                                                                              Although the pharmacokinetics of LUCEMYRA have not been systematically evaluated in patients who do not express the drug metabolizing enzyme CYP2D6, it is likely that the exposure to LUCEMYRA would be increased similarly to taking strong CYP2D6 inhibitors (approximately 28%).

Monitor adverse events such as orthostatic hypotension and bradycardia in known CYP2D6 poor metabolizers. Approximately 8% of Caucasians and 3–8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers.

 OVERDOSAGE

Overdose with LUCEMYRA may manifest as hypotension, bradycardia, and sedation. In the event of acute overdose, perform gastric lavage where appropriate. Dialysis will not remove a substantial portion of the drug.