SIXMO 74.2mg implant medication leaflet

Sixmo 74.2 mg implant

Each implant contains buprenorphine hydrochloride equivalent to 74.2 mg buprenorphine.

For the full list of excipients, see section 6.1.

Implant

White/ff-white to pale yellow, rod-shaped implant, 26.5 mm long and 2.4 mm in diameter.

Sixmo is indicated for substitution treatment for opioid dependence in clinically stable adult patientswho require no more than 8 mg/day of sublingual buprenorphine, within a framework of medical,social and psychological treatment.

Treatment must be under the supervision of a healthcare professional experienced in the managementof opioid dependence/addiction. Insertion and removal of the implants must be performed by aphysician who is competent in minor surgery and has been trained to conduct the insertion andremoval procedure. Appropriate precautions, such as the conduct of patient follow-up visits accordingto the patient's needs and the treating physician’s clinical judgement, should be taken during thetreatment.

Patients previously treated with sublingual buprenorphine or sublingual buprenorphine + naloxone,must be on stable doses between 2 to 8 mg/day for at least 30 days and deemed clinically stable by thetreating healthcare professional.

The following factors should be considered when determining clinical stability and suitability for

Sixmo treatment:

* period free from opioid drug abuse

* stability of living environment

* participation in a structured activity/job

* consistency in participation in recommended behavioural therapy/peer support programme

* consistency in compliance with clinic visit requirements

* minimal to no desire or need to abuse opioids

* period without episodes of hospitalisations (addiction or mental health issues), emergency roomvisits, or crisis interventions

* social support system

Sixmo should be used only in patients who are opioid tolerant. Each dose consists of four implants, forsubcutaneous insertion in the inner side of the upper arm.

The implants are intended to be in place for 6 months of treatment and provide a sustained delivery ofbuprenorphine. They are removed by the end of the sixth month.

Sublingual buprenorphine should be discontinued 12 to 24 hours prior to subcutaneous insertion of theimplants.

Criteria for the use of supplemental sublingual buprenorphine

It is possible that a subset of patients may require occasional supplemental sublingual buprenorphinesupport to achieve full control of opioid withdrawal symptoms and cravings, e.g. at times of personalstress or crisis.

The administration of additional buprenorphine sublingual doses should be considered by the treatingphysician if:

* the patient experiences withdrawal symptoms, e.g. sweating, lacrimation, yawning, nausea,vomiting, tachycardia, hypertension, piloerection, dilated pupils;

* in case of patient’s self-reported heroin use, other opioid use or craving and/ or urine samplespositive for opioids

Although some patients may require occasional supplemental dosing with buprenorphine, patientsshould not be provided with prescriptions for sublingual buprenorphine-containing products for as-needed use. Instead, patients who feel the need for supplemental dosing should be seen and evaluatedpromptly.

Treatment discontinuation criteria

The treating physician should consider implant removal if:

* the patient experiences severe or intolerable side effects (including severe precipitatedwithdrawal);

* signs of intoxication or overdose appear (miosis, lip cyanosis, sedation, bradycardia,hypotension, respiratory depression);

* the patient experiences lack of efficacy, as evidenced by lasting withdrawal symptoms thatrequire repeated management with sublingual buprenorphine

Patients who discontinue treatment with Sixmo should be switched back to their previous dose ofsublingual buprenorphine within 12 to 24 hours following removal of the implants (i.e. the dose fromwhich they were transferred prior to starting Sixmo treatment). The dissociation of buprenorphinefrom the µ-opioid receptors is expected to take up to several days after discontinuation of Sixmotreatment, which will prevent withdrawal symptoms immediately after removal of the implants.

If continued treatment is desired at the end of the first six-month treatment cycle, a new set of4 implants may be administered following removal of the old implants for one additional treatmentcycle of six months. The experience of a second treatment cycle is limited. There is no experience ofre-implantation beyond 12 months. Implants should be inserted in the inner side of the opposite upperarm, following the insertion steps below to locate the appropriate insertion site.

Implants for repeat treatment should be inserted subcutaneously as soon as possible after removal ofthe previous implants, preferably on the same day. If implants for repeat treatment are not inserted onthe same day as removal of previous implants, individuals should be maintained on a fixed dose of 2to 8 mg/day of sublingual buprenorphine, as clinically indicated, until repeat treatment occurs.

Sublingual buprenorphine should be discontinued 12 to 24 hours prior to insertion of four Sixmoimplants.

After one subcutaneous insertion in each arm (for a total of two treatments cycles), most patientsshould be transitioned back to their previous sublingual buprenorphine dose (i.e. the dose from whichthey were transferred to Sixmo treatment) for continued treatment. There are no prospective data with

Sixmo beyond two treatment cycles, and there is no experience with inserting the implants into othersites of the arm, sites other than the upper arm or re-insertion into previously-used sites.

Clinical studies of Sixmo did not include patients over 65 years and, therefore, the use of the productin this population is not recommended. The efficacy and safety of buprenorphine in elderly patients> 65 years has not been established. No recommendation on posology can be made.

Because buprenorphine levels cannot be adjusted during the treatment, Sixmo is contraindicated inpatients with severe hepatic impairment (Child-Pugh C) (sections pct. 4.3, pct. 4.4 and 5.2). Patients with mildto moderate hepatic impairment (Child-Pugh A and B) should be monitored for signs and symptoms oftoxicity or overdose caused by increased levels of buprenorphine (miosis, lip cyanosis, sedation,bradycardia, hypotension, respiratory depression).Patients who develop hepatic impairment whilebeing treated with Sixmo should be monitored for signs and symptoms of toxicity or overdose.

In case toxicity or overdose symptoms develop, the removal of the implants and transition to amedicinal product that allows dose adjustment are required.

Renal elimination plays a relatively small role (approximately 30%) in the overall clearance ofbuprenorphine and buprenorphine plasma concentrations were not increased in patients with renalimpairment.

Modification of the Sixmo dose is not required in patients with renal impairment. Caution isrecommended when dosing patients with severe renal impairment (creatinine clearance < 30 mL/min)(see sections 4.4 and 5.2).

The safety and efficacy of Sixmo in children under 18 years have not yet been established. No data areavailable. Sixmo should not be used in children aged 12 to less than 18 years of age because it doesnot represent a significant therapeutic benefit over existing treatments.

There is not relevant use of Sixmo in children from birth to less than 12 years of age in the indicationof substitution treatment for opioid dependence as it does not occur in the specified paediatricpopulation.

Subcutaneous use

Preparations for handling or administering the medicinal product

* The insertion and removal of the implants should take place under aseptic conditions.

* The patient should be able to lie on their back.

* It is recommended that the healthcare professional is in a seated position during the entireinsertion procedure so that the insertion site and the movement of the needle under the skin canbe clearly seen from the side. Only a healthcare professional who is competent in minor surgeryand is trained in the insertion of Sixmo should perform the procedure, using only the implantapplicator, with the recommended local anaesthetic available.

* One applicator is used to insert all four implants.

* Please note that an ultrasound and magnetic resonance imaging (MRI) facilities need to beavailable to the clinical site at which the insertion and removal of Sixmo occurs.

* Patients who have contraindications for MRI should be not allowed to receive the implant.

Equipment for subcutaneous insertion of Sixmo

The following equipment is needed for implant insertion under aseptic conditions:

* an examination table for the patient to lie on

* instrument stand covered with sterile drape

* adequate lighting, such as headlamp

* sterile fenestrated drape

* latex, talc-free sterile gloves

* alcohol pad

* surgical marker

* antiseptic solution, such as chlorhexidine

* local anaesthetic, such as 1% lidocaine with adrenaline 1:100 000

* 5 mL syringe with 25G×1.5' needle (0.5×38 mm)

* Adson single tooth tissue forceps

* #15 blade scalpel

* thin adhesive strip around 6 mm wide (butterfly strip)

* 100×100 mm sterile gauze

* adhesive bandages

* pressure bandage around 8 cm wide

* liquid adhesive

* 4 Sixmo implants

* 1 implant applicator

The implant applicator (disposable) and its parts are shown in Figure 1.

Figure 1

Instructions for subcutaneous insertion of Sixmo

Step 1: The patient should lie on their back, with the intended arm flexed at the elbow and externallyrotated, so that the hand is positioned next to the head. Identify the insertion site, which is at the innerside of the upper arm, about 80 to 100 mm (8 to 10 cm) above the medial epicondyle, in the sulcusbetween the biceps and triceps muscle. Having the patient flex the biceps muscle may facilitateidentification of the site (Figure 2).

Figure 2

Step 2: Clean the insertion site with an alcohol pad. Mark the insertion site with the surgical marker.

The implants will be inserted through a small 2.5 to 3 mm subcutaneous incision. Mark the channeltracks where each implant will be inserted by drawing 4 lines - with each line 40 mm long. Theimplants will be positioned in a close fan-shaped distribution 4 to 6 mm apart, with the fan openingtowards the shoulder (Figure 3).

Figure 3

Step 3: Put on sterile gloves and check the function of the implant applicator by removing theobturator from the cannula and relocking it. Clean the insertion site with an antiseptic solution, such aschlorhexidine. Do not blot or wipe away.

Apply the sterile fenestrated drape to the patient’s arm (Figure 4). Anaesthetise the insertion area atthe incision site and just under the skin, along the planned insertion channels, by injecting 5 mLlidocaine 1% with adrenaline 1:100 000. After determining that anaesthesia is adequate and effective,make a shallow incision 2.5 to 3 mm in length at incision site marking.

Figure 4

Step 4: Lift the edge of the incision opening with the toothed forceps. While applying counter-tractionto the skin, at a slight angle (no greater than 20 degrees), insert only the tip of the applicator into thesubcutaneous space (depth of 3 to 4 mm below the skin), with the bevel-up stop marking on thecannula facing upwards and visible with the obturator locked fully into the cannula (Figure 5).

Figure 5

Step 5: Lower the applicator to a horizontal position; lift the skin up with the tip of the applicator, butkeep the cannula in the subcutaneous connective tissue (Figure 6).

Figure 6

Step 6: While lifting, gently advance the applicator subcutaneously along the channel marking on theskin. Stop immediately once the proximal marking on the cannula has disappeared into the incision(Figures 7 and 8).

Figure 7

Figure 8

Step 7: While holding the cannula in place, unlock the obturator and remove the obturator. Insert oneimplant into the cannula (Figure 9), re-insert the obturator, and gently push the obturator forward(mild resistance should be felt) until the obturator stop line is level with the bevel-up stop marking,which indicates the implant is positioned at the tip of the cannula (Figure 10). Do not force theimplant beyond the end of the cannula with the obturator. There should be at least 5 mm betweenthe incision and the implant when the implant is properly positioned.

Figure 9

Figure 10

Step 8: While holding the obturator in place on the arm, retract the cannula along the obturator,leaving the implant in place (Figure 11). Note: Do not push the obturator. Withdraw the cannulauntil the hub is flush with the obturator, then twist the obturator clockwise to lock onto the cannula(Figure 12). Retract the applicator, bevel-up, until the distal marking of the cannula is visible at theincision opening (the sharp tip remaining in the subcutaneous space).

Figure 11

Figure 12

Step 9: Redirect the applicator to the next channel marking, while stabilizing the previously insertedimplant with your index finger, away from the sharp tip (Figure 13). Follow steps 6 through 9 for theinsertion of the three remaining implants through the same incision.

Figure 13

Step 10: Verify the presence of each implant (26.5 mm in length) by palpation of the patient’s armimmediately after the insertion, as shown in Figure 14. If you cannot feel each of the four implants, ordoubt their presence, use other methods to confirm the presence of the implant.

Figure 14

Step 11: Apply pressure to the incision site for approximately five minutes if necessary. Clean theincision site. Apply liquid adhesive to the skin margins and allow to dry before closing the incisionwith the thin adhesive strip around 6 mm wide (butterfly strip). Place a small adhesive bandage overthe insertion site. Apply a pressure bandage with sterile gauze to minimize bruising. Instruct thepatient that the pressure bandage can be removed after 24 hours and the adhesive bandage removed inthree to five days, and to apply an ice pack on the arm for 40 minutes every two hours for the first24 hours, then as needed.

Step 12: Complete the Patient Alert Card and give it to the patient to keep. Also, scan or input thedetails of the implant procedure into the patient’s medical records. Advise the patient on proper care ofthe insertion site.

Instruction for location of implants prior to removal

Verify the location of the implants by palpation. Non-palpable implants must be located prior toattempted removal. In the case of non-palpable implants, removal should be performed underultrasound guidance (following their localisation). Suitable methods for location include ultrasoundwith a high frequency linear array transducer (10 MHz or greater) or, in case ultrasound is notsuccessful, magnetic resonance imaging (MRI). Sixmo implants are not radiopaque and cannot be seenby X-ray or CT scan. Exploratory surgery without knowledge of the exact location of all implants isstrongly discouraged (see section 4.4).

Equipment for removal of Sixmo

Implants should be removed under aseptic conditions, whereby the following equipment is needed:

* an examination table for the patient to lie on

* instrument stand covered with sterile drape

* adequate lighting, such as headlamp

* sterile fenestrated drapes

* latex, talc-free, sterile gloves

* alcohol pad

* surgical marker

* antiseptic solution, such as chlorhexidine

* local anaesthetic, such as 1% lidocaine with adrenaline 1:100 000

* 5 mL syringe with 25G×1.5' needle (0.5×38 mm)

* Adson single tooth tissue forceps

* mosquito forceps

* two X-plant clamps (vasectomy fixation clamps with 2.5 mm ring diameter)

* iris scissors

* needle driver

* #15 blade scalpel

* sterile ruler

* 100×100 mm sterile gauze

* adhesive bandage

* pressure bandage around 8 cm wide

* sutures, such as 4-0 Prolene™ with an FS-2 cutting needle (may be absorbable)

Instructions for removal of Sixmo

Step 13: The patient should lie on their back, with the implant arm flexed at the elbow and externallyrotated, so that the hand is positioned next to the head. Reconfirm the location of the implants bypalpation. Clean removal site with alcohol pad prior to marking the skin. Using the surgical marker,mark the location of the implants and the location of the incision. The incision should be made parallelto the axis of the arm, between the second and third implants, to access the subcutaneous space(Figure 15).

Figure 15

Step 14: Put on sterile gloves. Using aseptic technique, place the sterile equipment on the sterile fieldof the instrument stand. Clean the removal site with an antiseptic solution, such as chlorhexidine. Donot blot or wipe away. Apply the sterile drape to the patient’s arm. Anaesthetise the incision site andthe subcutaneous space containing the implants (for example, by injecting 5 to 7 mL lidocaine 1%with adrenaline 1:100 000).

NOTE: Be sure to inject the local anaesthetic deep to the centre of the implants; this will effectivelylift the implants toward the skin, facilitating removal of the implants. After determining theanaesthesia is adequate and effective, make a 7 to 10 mm incision with a scalpel, parallel to the axis ofthe arm, between the second and third implants.

Step 15: Pick up the skin edge with Adson single toothed tissue forceps and separate the tissues aboveand below the visible implant, using an iris scissors or a curved mosquito forceps (Figure 16).

Grasp the centre of the implant with the X-plant clamp(s) (Figure 17) and apply gentle traction. If theimplant is encapsulated, or you see dimpling, use the scalpel to shave the adhering tissue to release theimplant.

Figure 16

Figure 17

Step 16: After removal of each implant, confirm that the entire 26.5 mm long implant has beenremoved by measuring its length. Follow steps 15 and 16 for the removal of the remaining implantsthrough the same incision. The same technique is employed for the removal of protruding or partiallyexpelled implants. Exploratory surgery without knowledge of the exact location of all implants isstrongly discouraged (see section 4.4).

Step 17: After removal of all implants, clean the incision site. Close the incision with sutures. Place anadhesive bandage over the incision. Use the sterile gauze and apply gentle pressure to the incision site,for five minutes, to ensure haemostasis. Apply a pressure bandage with sterile gauze to minimizebruising. Instruct the patient that the pressure bandage can be removed after 24 hours and the adhesivebandage in three to five days. Counsel the patient on proper aseptic wound care. Instruct the patient toapply an ice pack to the arm for 40 minutes every two hours for first 24 hours, then as needed.

Schedule an appointment for the sutures to be removed.

Step 18: Disposal of Sixmo implants should be in accordance with local requirements as it containsbuprenorphine.

If implant(s) or implant fragment(s) are not removed during a removal attempt, the patient shouldundergo imaging for localisation as soon as is feasible with the subsequent removal attempt performedon the same day as localisation. If localisation and a second removal attempt are not performed on thesame day as the initial removal attempt, the wound should be closed with sutures in the interim.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Severe respiratory insufficiency.

Acute alcoholism or delirium tremens (see section 4.5).

Concomitant administration of opioid antagonists (naltrexone, nalmefene) for the treatment of alcoholor opioid dependence (see section 4.5).

Patients with a history of keloid or hypertrophic scar formation should not undergo subcutaneousinsertion (see section 4.4).

Patients who have contraindications for MRI.

Patients may experience somnolence, especially in the first week following insertion of the implantsand should be cautioned in this respect (see section 4.7).

The insertion site should be examined one week following implant insertion and regularly thereafterfor signs of infection or any problems with wound healing, including evidence of implant extrusionfrom the skin as well as misuse or abuse. The recommended visit schedule for most patients is afrequency of no less than once-monthly for continued counselling and psychosocial support.

Serious complications from insertion and removal of the implants

Rare but serious complications, including nerve damage and migration resulting in embolism anddeath, may result from improper insertion of the implants in the upper arm (see section 4.8).

Additional complications may include local migration, protrusion, expulsion and implant breakageafter insertion or during removal. Surgical intervention is necessary for removing an implant that hasmigrated.

Subcutaneous insertion is essential to confirm proper placement by palpation. If implants are placedtoo deeply (intramuscular or in the fascia) this may lead to neural or vascular injury upon insertion orremoval.

Infection may occur at the site of the insertion or removal. Excessive palpation shortly after insertionof the implants may increase the chance of infection. Improper removal carries risk of implant-siteinfection and implant breakage.

In rare cases, implants or partial implants could not be localized and were, therefore, not removed (seesection 4.2).

Expulsion of the implant

If spontaneous expulsion of the implant occurs after insertion, the following steps should be taken:

* An appointment for the patient should be scheduled to return to the inserting healthcareprofessional as soon as possible.

* The patient should be instructed to place the implant in a glass jar with a lid, store it safely awayfrom others, especially children, and bring it to the healthcare professional to determine whetherthe full implant has been expelled.

Buprenorphine can cause severe, possibly fatal, respiratory depression in children who areaccidentally exposed to it.

* If the patient returns the expelled implant, it should be measured to ensure that the entireimplant was expelled (26.5 mm in length).

* The incision site should be inspected for infection. If infected, it should be treated appropriatelyand be determined if remaining implants need to be removed.

* If the expelled implant is not intact, the healthcare professional should palpate the insertionlocation to identify the location of any remaining partial implant. The remaining partial implantshould be removed using the techniques described in section 4.2.

* If it is not possible to palpate the remaining implant, an ultrasound or MRI should be performedper techniques described in section 4.2.

* The healthcare professional must carefully monitor the patient until the implant is replaced toevaluate for withdrawal or other clinical indicators suggesting that supplemental sublingualbuprenorphine may be needed.

* The replacement implant(s) should be inserted in same arm either medially or laterally to in situimplants. Alternatively, replacement implant(s) may be inserted in the contralateral arm.

Misuse and diversion

Buprenorphine has the potential to be abused and is prone to criminal diversion. Sixmo is formulatedas a diversion and abuse deterrent formulation. Nevertheless, it is possible to extract the buprenorphinefrom the implant. These risks and the patient’s stability in treatment for opioid dependence should beconsidered when determining whether Sixmo is appropriate for the patient.

Abuse of buprenorphine poses a risk of overdose and death. This risk is increased with theconcomitant abuse of buprenorphine and alcohol and other substances, especially benzodiazepines.

All patients receiving Sixmo should be monitored for conditions indicative of diversion, orprogression of opioid dependence and addictive behaviours suggesting the need for more intensive andstructured treatment for substance use.

Dependence

Buprenorphine is a partial agonist at the µ (mu)-opioid receptor and chronic administration producesdependence of the opioid type. Studies in animals, as well as clinical experience, have demonstratedthat buprenorphine may produce dependence, but at a lower level than a full agonist, e.g. morphine.

If the implants are not immediately replaced upon removal, patients should be maintained onsublingual buprenorphine (2 to 8 mg/day), as clinically indicated, until Sixmo treatment is resumed.

Patients who elect to discontinue Sixmo treatment should be monitored for withdrawal syndrome, withconsideration given to use of a tapering dose of sublingual buprenorphine.

Precipitation of opioid withdrawal syndrome

The partial opioid agonist properties of buprenorphine may precipitate opioid withdrawal signs andsymptoms in persons who are currently physically dependent on full opioid agonists - such as heroin,morphine, or methadone - before the effects of the full opioid agonist have subsided. Verify thatpatients have completed an appropriate induction period with sublingual buprenorphine orbuprenorphine/naloxone, or are already clinically stable on buprenorphine or buprenorphine/naloxonebefore inserting the implants (see section 4.2).

Respiratory and central nervous system (CNS) depression

A number of cases of death due to respiratory depression have been reported while on buprenorphine,particularly when buprenorphine was used in combination with benzodiazepines (see section 4.5) orwhen buprenorphine was not used according to prescribing information. Deaths have also beenreported in association with concomitant administration of buprenorphine and other depressants suchas alcohol, gabapentinoids (such as pregabalin and gabapentin) (see section 4.5) or other opioids. Ifbuprenorphine is administered to some non-opioid dependent individuals, who are not tolerant to theeffects of opioids, potentially fatal respiratory depression may occur.

This product should be used with caution in patients with asthma or respiratory insufficiency (e.g.chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia,hypercapnia, pre-existing respiratory depression or kyphoscoliosis [curvature of spine leading topotential shortness of breath]).

Buprenorphine may cause drowsiness, particularly when taken together with alcohol or CNSdepressants (such as tranquilisers, sedatives or hypnotics) (see section 4.5).

Prior to initiating Sixmo therapy, the patient’s medical and treatment history, including use of non-opioid psychoactive substances, needs to be reviewed, in order to ensure that Sixmo treatment can besafely initiated.

Hepatitis and hepatic events

Cases of acute hepatic injury (including fatal cases) have been reported with the active substancebuprenorphine in opioid-dependent addicts both in clinical studies and in post marketing adversereaction reports, see section 4.8. The spectrum of abnormalities ranges from transient asymptomaticelevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenalsyndrome, hepatic encephalopathy and death. In many cases the presence of pre-existing hepaticimpairment (genetic disease, liver enzyme abnormalities, infection with hepatitis B or hepatitis Cvirus, alcohol abuse, anorexia, concomitant use of other potentially hepatotoxic medicinal products)and ongoing injecting drug use may have a causative or contributory role. These underlying factorsincluding confirmation of viral hepatitis status must be taken into consideration before prescribing

Sixmo and during treatment. When a hepatic event is suspected, liver function evaluation is required,including consideration whether to discontinue treatment with Sixmo. If the treatment is continued,hepatic function should be monitored closely.

Buprenorphine is extensively metabolized in the liver. In a pharmacokinetic study with sublingualbuprenorphine, buprenorphine plasma levels were found to be higher and the half-life was found to belonger in patients with moderate and severe hepatic impairment, but not in patients with mild hepaticimpairment (see section 5.2). Patients with mild to moderate hepatic impairment should be monitoredfor signs and symptoms of toxicity, or overdose caused by increased levels of buprenorphine (seesection 4.2). Sixmo is contraindicated in patients with severe hepatic impairment (see section 4.3).

Treatment of acute pain during therapy

While on Sixmo, situations may arise where patients need acute pain management or anaesthesia.

Treat these patients with a non-opioid analgesic whenever possible. Patients requiring opioid therapyfor analgesia may be treated with a high-affinity full opioid analgesic under the supervision of ahealthcare professional, with particular attention to respiratory function. Higher doses may be requiredfor analgesic effect. Therefore, a higher potential for toxicity exists with opioid administration. Ifopioid therapy is required as part of anaesthesia, patients should be continuously monitored in ananaesthesia care setting by persons not involved in the conduct of the surgical or diagnostic procedure.

The opioid therapy must be provided by healthcare professionals trained in the use of anaestheticmedicinal products and the management of the respiratory effects of potent opioids, specifically theestablishment and maintenance of a patent airway and assisted ventilation.

Renal elimination may be prolonged since 30% of the administered dose is eliminated by the renalroute. Metabolites of buprenorphine accumulate in patients with renal failure. Caution isrecommended when dosing patients with severe renal impairment (creatinine clearance < 30 mL/min)(see sections 4.2 and 5.2).

Medicinal products that inhibit the enzyme CYP3A4 may give rise to increased concentrations ofbuprenorphine. Patients receiving Sixmo should be closely monitored for signs of toxicity if combinedwith potent CYP3A4 inhibitors (e.g. protease inhibitors like ritonavir, nelfinavir or indinavir, or azoleantifungals such as ketoconazole and itraconazole, or macrolide antibiotics). The healthcareprofessional should review the patient’s treatment history for concomitant use of CYP3A4 inhibitorsprior to initiating Sixmo treatment to determine suitability (see section 4.5).

General precautions relevant to the administration of opioids

Opioids may produce orthostatic hypotension in ambulatory patients.

Opioids may elevate cerebrospinal fluid pressure, which may cause seizures, so opioids should be usedwith caution in patients with head injury, intracranial lesions, other circumstances where cerebrospinalpressure may be increased, or history of seizure.

Opioids should be used with caution in patients with hypotension, prostatic hypertrophy or urethralstenosis.

Opioid-induced miosis, changes in the level of consciousness, or changes in the perception of pain as asymptom of disease may interfere with patient evaluation or obscure the diagnosis or clinical course ofconcomitant disease.

Opioids should be used with caution in patients with myxoedema, hypothyroidism or adrenal corticalinsufficiency (e.g. Addison's disease).

Opioids have been shown to increase intracholedochal pressure, and should be used with caution inpatients with dysfunction of the biliary tract.

Opioids should be administered with caution to elderly or debilitated patients.

The concomitant use of monoamine oxidase inhibitors (MAOI) might produce an exaggeration of theeffects of opioids, based on experience with morphine (see section 4.5).

Serotonin syndrome

Concomitant administration of Sixmo and other serotonergic agents, such as MAO inhibitors, selectiveserotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) ortricyclic antidepressants may result in serotonin syndrome, a potentially life-threatening condition (seesection 4.5).

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation ofthe patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability,neuromuscular abnormalities, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should beconsidered depending on the severity of the symptoms.

Skin

Sixmo should also be administered with caution in patients with a history of connective tissue disease(e.g. scleroderma) or history of recurrent methicillin-resistant Staphylococcus aureus infections.

Sixmo is contraindicated in patients with a history of keloid or hypertrophic scar formation at the sitewhere Sixmo would be implanted, as difficulties in retrieving the implant are possible (see section4.3).

No interaction studies have been performed with Sixmo.

Buprenorphine should not be administered together with:

* Opioid antagonists: naltrexone and nalmefene can block the pharmacological effects ofbuprenorphine. Co-administration during buprenorphine treatment is contraindicated due to thepotentially dangerous interaction that may precipitate a sudden onset of prolonged and intenseopioid withdrawal symptoms (see section 4.3).

* Alcoholic drinks or medicinal products containing alcohol, as alcohol increases the sedativeeffect of buprenorphine. Sixmo is contraindicated in acute alcoholism (see section 4.3).

Buprenorphine should be used cautiously when co-administered with:

* Benzodiazepines: This combination may result in death due to respiratory depression of centralorigin. Therefore, doses must be limited and this combination must be avoided in cases wherethere is a risk of misuse. Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking this product, and should also becautioned to use benzodiazepines concurrently with this product only as directed by theirhealthcare professional (see section 4.4).

* Gabapentinoids: This combination may result in death due to respiratory depression. Therefore,dosages must be closely monitored and this combination must be avoided in cases where thereis a risk of misuse. Patients should be cautioned to use gabapentinoids (such as pregabalin andgabapentin) concurrently with this product only as directed by their physician (see section 4.4).

* Other CNS depressants: Other opioid derivatives (e.g. methadone, analgesics and antitussives),certain antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics other thanbenzodiazepines, neuroleptics, clonidine and related substances: these combinations increase

CNS depression. The reduced level of alertness can make driving and using machines hazardous(see section 4.7).

* Opioid analgesics: Adequate analgesia may be difficult to achieve when administering a fullopioid agonist in patients receiving buprenorphine. Therefore, the potential to overdose with afull agonist exists, especially when attempting to overcome buprenorphine partial agonisteffects, or when buprenorphine plasma levels are declining (see section 4.4).

* CYP3A4 inhibitors and inducers: Buprenorphine is metabolized to norbuprenorphine primarilyby CYP3A4; therefore, potential interactions may occur when buprenorphine is givenconcurrently with medicinal products that affect CYP3A4 activity. CYP3A4 inhibitors mayinhibit the metabolism of buprenorphine resulting in increased Cmax and AUC of buprenorphineand norbuprenorphine. Patients treated with CYP inhibitors (e.g. ritonavir, ketoconazole,itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, verapamil, diltiazem,amiodarone, amprenavir, fosamprenavir, aprepitant, fluconazole, erythromycin and grapefruitjuice) should be monitored for signs and symptoms of toxicity or overdose (miosis, lip cyanosis,sedation, bradycardia, hypotension, respiratory depression). In case toxicity or overdosesymptoms are observed, the removal of the implants and transition to a medicinal product thatallows dose adjustment are required.

* Similarly, inducers of CYP3A4 (e.g. phenobarbital, carbamazepine, phenytoin, rifampin) mayhave the potential to reduce buprenorphine plasma concentrations because of increasedmetabolism of buprenorphine to norbuprenorphine.

* Monoamine oxidase inhibitors (MAOI): Possible exacerbation of the effects of opioids, basedon experience with morphine.

* Serotonergic medicinal products, such as MAO inhibitors, selective serotonin re-uptakeinhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclicantidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, isincreased (see section 4.4).

There are no or limited data from the use of buprenorphine in pregnant women. Studies in animalshave shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Towards the end of pregnancy buprenorphine may induce respiratory depression in the newborn infanteven after a short period of administration. Long-term administration of buprenorphine during the lastthree months of pregnancy may cause a withdrawal syndrome in the neonate (e.g. hypertonia, neonataltremor, neonatal agitation, myoclonus or convulsions). The syndrome may be milder and moreprotracted than that from short acting full μ-opioid agonists. The syndrome is generally delayed forseveral hours to several days after birth. The nature of the syndrome may vary depending upon themother’s drug use history.

Due to the long half-life of buprenorphine, neonatal monitoring for several days should be consideredat the end of pregnancy, to prevent the risk of respiratory depression or withdrawal syndrome inneonates.

Due to the inflexibility with regard to dose increases and to the increased dose requirements duringpregnancy, Sixmo is not considered to be an optimal treatment choice for pregnant women, thereforetreatment with Sixmo should not be started in pregnant women. Sixmo is not recommended duringpregnancy and in women of childbearing potential not using contraception. If pregnancy occurs duringtreatment with Sixmo the benefit to the patient should be weighed against the risk to the foetus.

Generally, other buprenorphine treatments/formulations are considered more appropriate in thissituation.

Buprenorphine and its metabolites are excreted in human milk to such an extent that effects on thebreastfed newborns/infants are likely. Therefore, breastfeeding should be discontinued duringtreatment with Sixmo.

There are no or limited data on effects of buprenorphine on human fertility (see section 5.3).

Buprenorphine can influence the ability to drive and use machines and may impair the mental orphysical abilities required for the performance of potentially dangerous tasks such as driving a car oroperating machinery. This product may cause dizziness, somnolence or sedation especially at the startof treatment.

Plasma concentrations of buprenorphine after insertion of Sixmo are highest during the first 24 to48 hours. In particular, patients may experience somnolence for up to one week after subcutaneousinsertion; therefore, they should be cautioned about driving or operating hazardous machineryespecially during this time period. Before engaging driving or operating hazardous machinery patientsshould be reasonably certain that Sixmo does not adversely affect their ability to engage in suchactivities.

Adverse drug reactions were categorized as implant or non-implant adverse reactions.

The most frequent non-implant adverse reactions in clinical studies with Sixmo were headache (5.8%),constipation (5.5%) and insomnia (3.9%). These are common adverse reactions with buprenorphine.

Common implant site related adverse reactions such as implant site pain, pruritus, haematoma,haemorrhage, erythema and scar were reported in 25.9% and 14.1% of patients in the double-blind andextension studies, respectively.

Adverse reactions reported in clinical studies and post-marketing data for buprenorphine, including

Sixmo, are listed in the following Table 1. These adverse reactions are presented by MedDRA systemorgan class, preferred term, and frequency.

Frequency categories are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot beestimated from the available data).

Table 1: Adverse reactions listed by body system

System organ class Frequency Adverse reactions

Infections and infestations common Viral infection,

Bronchitis**,

Infection**,

Influenza**,

Pharyngitis**,

Rhinitis**uncommon Cellulitis,

Skin infection,

Peritonsillar abscess,

Rash pustular,

Urinary tract infection,

Vulvovaginal mycotic infection,

Implant site infection*,

Implant site abscess*

Blood and lymphatic uncommon Lymphadenopathy,system disorders Neutropenia

Metabolism and nutrition common Decreased appetitedisorders uncommon Abnormal weight gain,

Dehydration,

Increased appetite

Psychiatric disorders common Insomnia,

Anxiety,

Hostility**,

Nervousness**,

Paranoia**uncommon Depression,

Libido decreased,

Sleep disorder,

Apathy,

Euphoric mood,

Orgasmic sensation decreased,

Restlessness,

Irritability,

Drug dependence***,

Agitation***,

Thinking abnormal***

Nervous system disorders common Headache,

Dizziness,

Somnolence,

Hypertonia**,

Syncope**uncommon Hypoaesthesia,

Migraine,

Depressed level of consciousness,

Hypersomnia,

Paraesthesia,

Tremor

Eye disorders common Mydriasis**uncommon Eye discharge,

Lacrimal disorder,

Vision blurredcommon Palpitations**

System organ class Frequency Adverse reactions

Cardiac disorders uncommon Atrial flutter,

Bradycardia

Vascular disorders common Hot flush,

Vasodilatation**,

Hypertension**

Respiratory, thoracic and common Cough**,mediastinal disorders Dyspnoea**uncommon Respiratory depression,

Yawning

Gastrointestinal disorders common Constipation,

Nausea,

Vomiting,

Diarrhoea,

Abdominal pain,

Gastrointestinal disorder**,

Tooth disorder**uncommon Dry mouth,

Dyspepsia,

Flatulence,

Haematochezia

Skin and subcutaneous common Hyperhidrosistissue disorders uncommon Cold sweat,

Dry skin,

Rash,

Skin lesion,

Ecchymosis*

Musculoskeletal and common Bone pain**,connective disorders Myalgia**uncommon Muscle spasms,

Limb discomfort,

Musculoskeletal pain,

Neck pain,

Pain in extremity,

Temporomandibular joint syndrome,

Arthralgia***

Renal and urinary disorders uncommon Urinary hesitation,

Micturition urgency,

Pollakisuria

Reproductive system and uncommon Dysmenorrhoea,breast disorders Erectile dysfunction

General disorders and common Fatigue,administration site Chills,conditions Asthenia,

Pain,

Implant site haematoma*,

Implant site pain*,

Implant site pruritus*,

Implant site haemorrhage*,

Implant site erythema*,

Implant site scar*,

Chest pain**,

Malaise***,

Withdrawal syndrome***

System organ class Frequency Adverse reactionsuncommon Oedema peripheral,

Discomfort,

Face oedema,

Feeling cold,

Pyrexia,

Swelling,

Implant site oedema*,

Implant site reaction*,

Implant expulsion*,

Impaired healing*,

Implant site paraesthesia*,

Implant site rash*,

Scarring *

Investigations common alanine aminotransferase increaseduncommon Aspartate aminotransferase increased,

Weight decreased,

Blood lactate dehydrogenase increased,

Gamma-glutamyl-transferase increased,

Weight increased,

Blood alkaline phosphatase decreased,

Amylase increased,

Blood bicarbonate increased,

Blood bilirubin increased,

Blood cholesterol decreased,

Blood glucose increased,

Haematocrit decreased,

Haemoglobin decreased,

Lipase increased,

Lymphocyte count decreased,

Mean cell haemoglobin increased,

Mean cell volume abnormal,

Monocyte count increased,

Neutrophil count increased,

Platelet count decreased,

Red blood cell count decreased

Injury, poisoning and common Procedural pain*,procedural complications Procedural site reaction*uncommon Post procedural complication (*),

Contusion (*),

Wound dehiscence*,

Migration of implant***,

Implant breakage***

* Implant site adverse drug reaction(*) Observed as implant and non-implant site adverse drug reaction

** Reported with other approved buprenorphine only medicinal product

*** Post-marketing data only

Risk of serious complications of insertion and removal of implants

Rare but serious complications including nerve damage and migration resulting in embolism and deathmay result from improper insertion of implants (see section 4.4). In the post-marketing setting, 2 caseswere reported where implants had locally migrated from the insertion site. In 3 patients treated inclinical studies, and in 1 patient treated during post-marketing, implants or fragments could not belocated and were, therefore, not removed at the end of the treatment. In clinical studies and from post-marketing data 7 cases of clinically relevant implant breakage (i.e. breakage associated with anadverse reaction) were observed.

Risk of expulsion

Improper insertions or infections may lead to protrusion or expulsion. Few cases of protrusion orexpulsion of implants, mainly attributed to improper insertion technique, were reported in clinicalstudies with Sixmo (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The manifestations of acute buprenorphine overdose include pinpoint pupils, sedation, hypotension,respiratory depression and death.

Priorities are the re-establishment of a patient and protected airway and institution of assistedventilation, if needed. Supportive measures (including oxygen, vasopressors) should be employed inthe management of circulatory shock and pulmonary oedema as indicated. Cardiac arrest orarrhythmias will require advanced life support techniques.

The opioid antagonist naloxone is a specific antidote to respiratory depression resulting from opioidoverdose. Naloxone may be of value for the management of buprenorphine overdose. Higher thannormal doses and repeated administration may be necessary.

Healthcare professionals should consider the potential role and contribution of buprenorphine whengiven in conjunction with other CNS depressant medicinal products, CYP3A4 inhibitors, other opioidsand in cases of hepatic impairment when determining whether the implants should be removed (seesections 4.4 and 4.5).

Pharmacotherapeutic group: Other nervous system drugs, Drugs used in opioid dependence, ATC code:

N07BC01

Buprenorphine is an opioid partial agonist/antagonist which binds to the μ (mu) and κ (kappa)receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversibleproperties at the µ receptors which, over a prolonged period, minimises the need for use of otheropioids.

During clinical pharmacologic studies in opioid-dependent patients, buprenorphine shows ceilingeffects on a number of pharmacodynamics and safety parameters. It has a relatively wide therapeuticwindow as a consequence of its partial agonist/antagonist properties, which attenuates suppression ofcardiovascular and respiratory function.

The safety and efficacy of buprenorphine implantswas investigated in 3 double-blind Phase 3 clinicalstudies in which a total of 309 patients were treated with Sixmo for up to 6 months (1 implant cycle).

Of these 309 patients, 107 patients were treated for an additional 6 months in extension studies (i.e. for2 implant cycles).

The demonstration of efficacy relies primarily on study PRO-814, a randomized, double-blind andactive-controlled Phase 3 study in adult patients who met DSM-IV-TR criteria for opioid dependenceand who were clinically stabilised on sublingual buprenorphine. In this study, approximately 75% ofpatients reported prescription opioids as the primary opioid of abuse, and 21% of patients reportedheroin as the primary opioid of abuse. The implant time was 24 weeks. This study enrolled 84 patientsin the Sixmo group and 89 patients in the sublingual buprenorphine group, with a median age (range)of 36 (21 to 63) years and 37 (22 to 64) years in the Sixmo and sublingual buprenorphine groups,respectively. In this double-blind and double-dummy study, patients maintained on doses of sublingualbuprenorphine of 8 mg/day or less were transferred to 4 Sixmo implants (and daily sublingualplacebo), or sublingual buprenorphine 8 mg/day or less (and 4 placebo implants). The primaryendpoint was proportion of responders, defined as patients with no more than 2 of 6 months withevidence of illicit opioid use based on a composite of both urine and self-report results. This endpointwas considered to be of clinical relevance in the targeted indication. Sixmo was shown to be non-inferior to sublingual buprenorphine, the proportion of responders being 87.6% in the sublingualbuprenorphine and 96.4% in the Sixmo group. Furthermore, after establishment of non-inferiority,superiority of Sixmo over sublingual buprenorphine was tested and established (p=0.034). Retention intreatment was high, with 96.4% of Sixmo patients and 94.4% of sublingual buprenorphine patientscompleting the study.

Two additional randomised, double-blind, placebo-controlled Phase 3 studies provide supportive dataon efficacy and pharmacokinetics (PK) (Studies PRO-805 and PRO-806). In both studies adultpatients with opioid dependence who were new entrants to buprenorphine treatment were treated over24 weeks with 4 Sixmo or 4 placebo implants. Patients not adequately treated with the 4 implant dosecould receive a fifth implant. Study PRO-806 included an open-label comparator arm with sublingualbuprenorphine (12 to 16 mg/day). Patients in all groups were allowed to use supplemental sublingualbuprenorphine to control potential withdrawal symptoms/cravings according to pre-specified criteria.

Patient characteristics in these studies are shown below.

Table 2: Patient characteristics in the studies PRO-805 and PRO-806

Study PRO-805 Study PRO-806

Sixmo Placebo Sixmo Placebo sublingual

N=108 N=55 N=114 N=54 buprenorphine

N=119

Median age 33 (19 - 62) 39 (20 - 61) 36 (19 - 60) 33 (19 - 59) 32 (18 - 60)(range), years

Primary opioid ofabuse, n (%)

Heroin 69 (63.9%) 34 (61.8%) 76 (66.7%) 28 (51.9%) 75 (63.0%)

Prescription 39 (36.1%) 21 (38.2%) 38 (33.3%) 26 (48.1%) 43 (36.1%)*opioids

* For 1 patient (0.8%) primary opioid of abuse was “other”.

The primary efficacy endpoint in both studies was the cumulative distribution function (CDF) of thepercentage of urine samples that were negative for illicit opioids (as evaluated through thrice weeklyurine toxicology and patient self-reported opioid use).

In study PRO-805, the primary endpoint was the CDF of the percentage of urine samples that werenegative for illicit opioids over weeks 1 to 16, while the CDF over weeks 17 to 24 was evaluated assecondary endpoint.

Table 3: Percentage of opioid-negative urine samples for weeks 1 to 16 and weeks 17 to 24,

Study PRO-805 (ITT)

Percentage of negative results Sixmo Placebo

N=108 N=55

Weeks 1 to 16

Mean (SE) 40.4 (3.15) 28.3 (3.97)

CI of mean 34.18, 46.68 20.33, 36.26

Median (Range) 40.7 (0, 98) 20.8 (0, 92)

Weeks 17 to 24

Mean (SE) 29.0 (3.34) 10.7 (3.19)

CI of mean 22.41, 35.66 4.33, 17.12

Median (Range) 4.4 (0, 100) 0.0 (0, 92)

CI=confidence interval, ITT=intent-to-treat, N=number of subjects, SE=standard error

In the analysis of the CDF (weeks 1 to 16), a statistically significant difference between treatments(p=0.0361) was seen, which was in favour of Sixmo.

Figure 1: Cumulative distribution function of the percentage of urine samples negative foropioids in weeks 1-16, Study PRO-805 (ITT)

ITT=intent-to-treat

Buprenorphine was not included in urine toxicology assessments.

Study PRO-806 had two co-primary endpoints, which were the CDF of the percentage of urinesamples that were negative for illicit opioids for Weeks 1 to 24 in the Sixmo and placebo groups (co-primary 1), and the CDF of the percentage of urine samples that were negative for illicit opioids for

Weeks 1 to 24 in the Sixmo and placebo groups, with imputation based on illicit drug self-report data(co-primary 2).

Table 4: Percentage of opioid-negative urine samples for weeks 1 to 24, Study PRO-806 (ITT)

Percentage of negative Sixmo Placebo Sublingualresults N=114 N=54 buprenorphine

N=119

Mean (SE) 31.21 (2.968) 13.41 (2.562) 33.48 (3.103)

CI of mean 25.33, 37.09 8.27, 18.55 27.33, 39.62

Median (Range) 20.28 (0.0, 98.6) 9.03 (0.0, 97.3) 16.33 (0.0, 98.6)

CI=confidence interval, ITT=intent-to-treat, N=number of subjects, SE=standard error

In the analysis of the CDF (co-primary endpoint 1), a statistically significant difference betweentreatments (p<0.0001) was seen, which was in favour of Sixmo.

Figure 2: Cumulative distribution function of the percentage of urine samples negative foropioids in weeks 1-24 (co-primary endpoint 1), Study PRO-806 (ITT Population)

ITT=intent-to-treat, SL BPN = sublingual buprenorphine

Buprenorphine was not included in urine toxicology assessments.

The CDF results for co-primary endpoint 2 were fundamentally the same as for endpoint 1(p < 0.0001).

A key secondary endpoint in Study PRO-806 was the difference in proportions of urine samples thatwere negative for opioids over 24 weeks for Sixmo versus sublingual buprenorphine. Despite the useof an open-label comparator arm, this endpoint is considered robust, as it is based on urine toxicology.

In this analysis, the percentage of opioid negative urines in the sublingual buprenorphine group wasvery similar to the results in the Sixmo group (33% versus 31%), and non-inferiority of Sixmo tosublingual buprenorphine was shown.

In Studies PRO-805 and PRO-806, 62.0% and 39.5% of Sixmo-treated subjects required supplemental

SL buprenorphine. The mean doses per week in Sixmo subjects in PRO-805 and PRO-806 studieswere 5.16 mg and 3.16 mg, with relatively low mean days of use per week of 0.45 and 0.31,respectively. In each of the two studies, the proportion of subjects requiring supplemental SL BPNwas significantly higher in the placebo group than in the Sixmo group (90.9% and 66.7% of subjects,with mean days of use per week of 2.17 and 1.27, in PRO-805 and PRO-806, respectively).

Retention in treatment was high in the Sixmo groups, with 65.7% and 64.0% of patients completingstudies PRO-805 and PRO-806, respectively.

The majority of patients (around 80%) in both studies were adequately treated with 4 implants; around20% of patients required a dose increase with a fifth implant.

In a subset of patients, Sixmo implants broke during implant removal. Breakage rates decreased instudies using the current technique and training. Generally, breakage was not perceived as a safetyconcern to the patient by the investigator.

Table 5: Implant breakage in Sixmo double-blind Phase 3 studies

Current technique and training

PRO-806 PRO-811 PRO-814

Sixmo Sixmo Sixmo

N= 99 N=78 N=82

Number (%) of broken implants 71 (17.0%) 81 (25.0%) 35 (10.7%)

Number (%) of patients withbroken implant(s) 42 (42.4%) 38 (48.7%) 22 (26.8%)

N=number of patients with data available.

Non-Caucasian population

The clinical experience with Sixmo in non-Caucasian patients is currently limited.

The European Medicines Agency has waived the obligation to submit the results of studies with

Sixmo in all subsets of the paediatric population for the maintenance treatment of opioid dependence(see section 4.2).

The Sixmo PK was assessed in opioid-dependent patients treated with Sixmo in studies TTP-400-02-01, PRO-810, PRO-805, PRO-806, PRO-807 and PRO-811. Prior to entry into acute studies PRO-805,

PRO-806, PRO-810 and TTP-400-02-01, patients were treatment naïve adults, with moderate tosevere opioid dependency. In the majority of patients, heroin was the primary opioid of use. After

Sixmo implant insertion, an initial buprenorphine peak was observed and the median Tmax occurred at12 hours after insertion. After the initial buprenorphine peak, the plasma buprenorphine concentrationsdecreased slowly and steady-state plasma buprenorphine concentrations were reached byapproximately week 4. Mean steady-state plasma buprenorphine concentrations were consistent acrossall clinical studies, at approximately 0.5 to 1 ng/mL (with the 4-implant dose), and were maintainedfor approximately 20 weeks (week 4 through week 24) in a 24-week treatment period. At steady state,a small decrease in buprenorphine concentrations was also recorded between week 4 and week 24.

Generally, concentrations were comparable to the trough buprenorphine concentration of 8 mg per daysublingual buprenorphine.

Plasma buprenorphine concentrations after Sixmo are illustrated in figure 3. Mean plasmabuprenorphine concentrations up to day 28 are based on data from the relative bioavailability study

PRO-810 (which had intensive PK sampling), while concentrations after day 28 are based on pooleddata from studies PRO-805, PRO-806, PRO-807 and PRO-811.

Figure 3: Plasma buprenorphine concentrations after insertion of Sixmo (concentrations up today 28 are based on study PRO-810, while concentrations after day 28 are based onstudies PRO-805, PRO-806, PRO-807 and PRO-811)

Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.

Buprenorphine undergoes N-dealkylation to its major pharmacologically active metabolitenorbuprenorphine and subsequent glucuronidation. The formation of norbuprenorphine was initiallyfound to be performed by CYP3A4; subsequent studies also demonstrated the involvement of

CYP2C8. Both buprenorphine and norbuprenorphine can further undergo glucuronidation by UDP-glucuronosyltransferases.

A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) andfaeces (69%) collected up to 11 days after dosing. Almost all of the dose was accounted for in terms ofbuprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites. In urine, most ofthe buprenorphine and norbuprenorphine was conjugated (buprenorphine: 1% free and 9.4%conjugated; norbuprenorphine: 2.7% free and 11% conjugated). In faeces, almost all of thebuprenorphine and norbuprenorphine were free (buprenorphine: 33% free and 5% conjugated;norbuprenorphine: 21% free and 2% conjugated).

Buprenorphine has a mean elimination half-life from plasma ranging from 24 to 48 hours.

The effect of hepatic impairment on the pharmacokinetics of Sixmo has not been studied.

Buprenorphine is extensively metabolized in the liver and increased plasma levels were found to beincreased in patients with moderate and severe hepatic impairment.

Sixmo is contraindicated in patients with severe hepatic impairment.

Renal elimination plays a relatively small role (approximately 30%) in the overall clearance ofbuprenorphine and buprenorphine plasma concentrations were not increased in patients with renalimpairment. No Sixmo dose adjustment is therefore considered necessary for patients with renalimpairment.

Clinical studies of Sixmo did not include patients over 65 years; therefore, the use of the product inthis population is not recommended. The efficacy and safety of buprenorphine in elderly patients> 65 years has not been established.

A standard battery of genotoxicity tests conducted on extracts of Sixmo and ethylene vinyl acetate(EVA) placebo implants was negative. Literature data indicated no genotoxic properties ofbuprenorphine.

There is no suspicion of carcinogenicity based on the clinical use of buprenorphine.

No published information is available regarding a potential effect of buprenorphine on male andfemale fertility. Studies in animals have shown reproductive toxicity.

When pregnant rats were exposed to buprenorphine through osmotic minipumps from gestation day 7onwards, maternal food and water consumption was reduced on gestation days 7 to 20. The mortalityindex was significantly increased in the buprenorphine groups. There was a greater occurrence ofresorptions and an increase in the number of stillbirths. Pups born tended to weigh less on postnatalday 1 compared with controls. Pups exposed to buprenorphine only during the prenatal period had asimilar body weight compared with controls in the first 3 postnatal weeks. However, pups exposed toopioids postnatally exhibited significant body weights reductions. Maternal exposure to buprenorphineincreased perinatal mortality and caused a delay in some development milestones in neonatal rats.

Ethylene vinyl acetate copolymer

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

Each implant is packaged individually into a PET/LDPE/Alu/LDPE-peelable foil laminate sachet.

Implant kit: 4 implants with 1 applicator

The removed implant contains a significant amount of residual buprenorphine.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

L. Molteni & C. dei F.lli Alitti Società di Esercizio S.p.A,

Strada Statale 67, Loc. Granatieri50018 Scandicci (Firenze),

Italy

EU/1/19/1369/001

Date of first authorisation: 20 June 2019

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.