Sixmo - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Sixmo 74.2 mg implant

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each implant contains buprenorphine hydrochloride equivalent to 74.2 mg of buprenorphine.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Implant

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

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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

4.2 Posology and method of administration

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

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 the treating 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 room visits, or crisis interventions
• • social support system

Posology

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

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

Treatment with Sixmo

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

Criteria for the use of supplemental sublingual buprenorphine

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

The administration of additional buprenorphine sublingual doses should be considered by the treating physician 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 samples

positive for opioids

Although some patients may require occasional supplemental dosing with buprenorphine, patients should 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 evaluated promptly.

Treatment discontinuation criteria

The treating physician should consider implant removal if:

• • the patient experiences severe or intolerable side effects (including severe precipitated

withdrawal);

• • 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 that

require repeated management with sublingual buprenorphine

Discontinuation

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

Retreatment

If continued treatment is desired at the end of the first six-month treatment cycle, a new set of 4 Sixmo implants may be administered following removal of the old implants for one additional treatment cycle of six months. The experience of a second treatment cycle is limited. There is no experience of reimplantation beyond 12 months. Implants should be inserted in the inner side of the opposite upper arm, 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 of the previous implants, preferably on the same day. If implants for repeat treatment are not inserted on the same day as removal of previous implants, individuals should be maintained on a fixed dose of 2 to 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 Sixmo implants.

After one subcutaneous insertion in each arm (for a total of two treatments cycles), most patients should be transitioned back to their previous sublingual buprenorphine dose (i.e. the dose from which they 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 Sixmo implants into other sites of the arm, sites other than the upper arm or re-insertion into previously-used sites. Special populations

Elderly

Clinical studies of Sixmo did not include patients over 65 years and, therefore, the use of the product in 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.

Hepatic impairment

Because buprenorphine levels cannot be adjusted during Sixmo treatment, Sixmo is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (sections 4.3, 4.4 and 5.2). Patients with mild to moderate hepatic impairment (Child-Pugh A and B) should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine (miosis, lip cyanosis, sedation, bradycardia, hypotension, respiratory depression). In case toxicity or overdose symptoms are observed, the removal of the implants and transition to a medicinal product that allows dose adjustment are required.

Patients who develop hepatic impairment while being 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 a medicinal product that allows dose adjustment are required.

Renal impairment

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

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

Paediatric population

The safety and efficacy of Sixmo in children under 18 years have not yet been established. No data are available.

Method of administration

Subcutaneous use

Preparations for handling or administering the medicinal product

• • The insertion and removal of Sixmo 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 entire

insertion procedure so that the insertion site and the movement of the needle under the skin can

be clearly seen from the side. Only a healthcare professional who is competent in minor surgery and is trained in the insertion of Sixmo should perform the procedure, using only the implant applicator, with the recommended local anaesthetic available.

• • One applicator is used to insert all four implants.
• • Please note that an ultrasound and MRI facilities need to be available 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 25Gx1.5" needle (0.5³⁸ 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 externally rotated, so that the hand is positioned next to the head. Identify the insertion site, which is at the inner side of the upper arm, about 80 to 100 mm (8 to 10 cm) above the medial epicondyle, in the sulcus between the biceps and triceps muscle. Having the patient flex the biceps muscle may facilitate identification of the site (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 channel tracks where each implant will be inserted by drawing 4 lines – with each line 40 mm long. The implants will be positioned in a close fan-shaped distribution 4 to 6 mm apart, with the fan opening towards the shoulder (Figure 3).

Figure 3

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

Apply the sterile fenestrated drape to the patient’s arm (Figure 4). Anaesthetise the insertion area at the incision site and just under the skin, along the planned insertion channels, by injecting 5 mL lidocaine 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.

Step 4 : Lift the edge of the incision opening with the toothed forceps. While applying counter-traction to the skin, at a slight angle (no greater than 20 degrees), insert only the tip of the applicator into the subcutaneous space (depth of 3 to 4 mm below the skin), with the bevel-up stop marking on the cannula 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, but keep 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 the skin. 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 one implant 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 the implant beyond the end of the cannula with the obturator. There should be at least 5 mm between the 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 cannula until 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 the incision 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 inserted implant with your index finger, away from the sharp tip (Figure 13). Follow steps 6 through 9 for the insertion 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 arm immediately after the insertion, as shown in Figure 14. If you cannot feel each of the four implants, or doubt 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 the incision site. Apply liquid adhesive to the skin margins and allow to dry before closing the incision with the thin adhesive strip around 6 mm wide (butterfly strip). Place a small adhesive bandage over the insertion site. Apply a pressure bandage with sterile gauze to minimize bruising. Instruct the patient that the pressure bandage can be removed after 24 hours and the adhesive bandage removed in three to five days, and to apply an ice pack on the arm for 40 minutes every two hours for the first 24 hours, then as needed.

Step 12 : Complete the Patient Alert Card and give it to the patient to keep. Also, scan or input the details of the implant procedure into the patient’s medical records. Advise the patient on proper care of the 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 to attempted removal. In the case of non-palpable implants, removal should be performed under ultrasound guidance (following their localisation). Suitable methods for location include ultrasound with a high frequency linear array transducer (10 MHz or greater) or, in case ultrasound is not successful, magnetic resonance imaging (MRI). Sixmo implants are not radiopaque and cannot be seen by X-ray or CT scan. Exploratory surgery without knowledge of the exact location of all implants is strongly 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 25Gx1.5" needle (0.5³⁸ 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 externally rotated, so that the hand is positioned next to the head. Reconfirm the location of the implants by palpation. 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 parallel to the axis of the arm, between the second and third implants, to access the subcutaneous space (Figure 15).

Step 14: Put on sterile gloves. Using aseptic technique, place the sterile equipment on the sterile field of the instrument stand. Clean the removal site with an antiseptic solution, such as chlorhexidine. Do not blot or wipe away. Apply the sterile drape to the patient’s arm. Anaesthetise the incision site and the 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 effectively lift the implants toward the skin, facilitating removal of the implants. After determining the anaesthesia is adequate and effective, make a 7 to 10 mm incision with a scalpel, parallel to the axis of the arm, between the second and third implants.

Step 15 : Pick up the skin edge with Adson single toothed tissue forceps and separate the tissues above and 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 the implant is encapsulated, or you see dimpling, use the scalpel to shave the adhering tissue to release the implant.

Figure 16

Figure 17

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

Step 17 : After removal of all implants, clean the incision site. Close the incision with sutures. Place an adhesive 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 minimize bruising. Instruct the patient that the pressure bandage can be removed after 24 hours and the adhesive bandage in three to five days. Counsel the patient on proper aseptic wound care. Instruct the patient to apply 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 contains buprenorphine.

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

4.3 Contraindications

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

Severe respiratory insufficiency

Severe hepatic impairment

Acute alcoholism or delirium tremens

Concomitant administration of opioid antagonists (naltrexone, nalmefene) for the treatment of alcohol or opioid dependence

Patients with a history of keloid or hypertrophic scar formation should not undergo subcutaneous insertion, as difficulties in retrieving the implant are possible.

Patients who have contraindications for MRI.

4.4 Special warnings and precautions for use

Treatment monitoring

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

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

Serious complications from insertion and removal of Sixmo implants

Rare but serious complications, including nerve damage and migration resulting in embolism and death, may result from improper insertion of drug implants in the upper arm. Additional complications may include local migration, protrusion, expulsion and implant breakage after insertion or during removal. Surgical intervention is necessary for removing an implant that has migrated.

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

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

In rare cases, implants or partial implants could not be localized and were, therefore, not removed (see section 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 healthcare

professional as soon as possible.

• • The patient should be instructed to place the implant in a glass jar with a lid, store it safely away

from others, especially children, and bring it to the healthcare professional to determine whether the full implant has been expelled.

Please note: Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.

• • If the patient returns the expelled implant, it should be measured to ensure that the entire

implant was expelled (26.5 mm in length).

• • The incision site should be inspected for infection. If infected, it should be treated appropriately and be determined if remaining implants need to be removed.
• • If the expelled implant is not intact, the healthcare professional should palpate the insertion location to identify the location of any remaining partial implant. The remaining partial implant should be removed using the techniques described in section 4.2 under “Instructions for removal of Sixmo”.
• • If it is not possible to palpate the remaining implant, an ultrasound or MRI should be performed per techniques described in section 4.2 under “Instructions for removal of Sixmo”.
• • The healthcare professional must carefully monitor the patient until the implant is replaced to evaluate for withdrawal or other clinical indicators suggesting that supplemental sublingual buprenorphine may be needed.
• • The replacement implant(s) should be inserted in same arm either medially or laterally to in situ

implants. 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 formulated as a diversion and abuse deterrent formulation. Nevertheless, it is possible to extract the buprenorphine from the Sixmo implant. These risks and the patient’s stability in treatment for opioid dependence should be considered when determining whether Sixmo is appropriate for the patient.

Abuse of buprenorphine poses a risk of overdose and death. This risk is increased with the concomitant abuse of buprenorphine and alcohol and other substances, especially benzodiazepines. All patients receiving Sixmo should be monitored for conditions indicative of diversion, or progression of opioid dependence and addictive behaviours suggesting the need for more intensive and structured treatment for substance use.

Dependence

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

If Sixmo implants are not immediately replaced upon removal, patients should be maintained on sublingual 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, with consideration 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 and symptoms 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 that patients have completed an appropriate induction period with sublingual buprenorphine or buprenorphine/na­loxone, or are already clinically stable on buprenorphine or buprenorphine/na­loxone before inserting Sixmo 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) or when buprenorphine was not used according to prescribing information. Deaths have also been reported in association with concomitant administration of buprenorphine and other depressants such as alcohol or other opioids. If buprenorphine is administered to some non-opioid dependent individuals, who are not tolerant to the effects 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 to potential shortness of breath]).

Buprenorphine may cause drowsiness, particularly when taken together with alcohol or CNS depressants (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 nonopioid psychoactive substances, needs to be reviewed, in order to ensure that Sixmo treatment can be safely initiated.

Hepatitis and hepatic events

Cases of acute hepatic injury (including fatal cases) have been reported with the active substance buprenorphine in opioid-dependent addicts both in clinical trials and in post marketing adverse reaction reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy and death. In many cases the presence of pre-existing hepatic impairment (genetic disease, liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, alcohol abuse, anorexia, concomitant use of other potentially hepatotoxic medicines) and ongoing injecting drug use may have a causative or contributory role. These underlying factors including 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.

Hepatic impairment

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

Treatment of acute pain during Sixmo 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 therapy for analgesia may be treated with a high-affinity full opioid analgesic under the supervision of a healthcare professional, with particular attention to respiratory function. Higher doses may be required for analgesic effect. Therefore, a higher potential for toxicity exists with opioid administration. If opioid therapy is required as part of anaesthesia, patients should be continuously monitored in an anaesthesia 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 anaesthetic medicinal products and the management of the respiratory effects of potent opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation.

Renal impairment

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

CYP3A inhibitors

Medicines that inhibit the enzyme CYP3A4 may give rise to increased concentrations of buprenorphine. Patients receiving Sixmo should be closely monitored for signs of toxicity if combined with potent CYP3A4 inhibitors (e.g. protease inhibitors like ritonavir, nelfinavir or indinavir, or azole antifungals such as ketoconazole and itraconazole, or macrolide antibiotics). The healthcare professional should review the patient’s treatment history for concomitant use of CYP3A4 inhibitors prior 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 used with caution in patients with head injury, intracranial lesions, other circumstances where cerebrospinal pressure may be increased, or history of seizure.

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

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

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

Opioids have been shown to increase intracholedochal pressure, and should be used with caution in patients 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 the effects 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, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5).

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the 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 be considered 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 site where Sixmo would be implanted, as difficulties in retrieving the implant are possible (see section 4.3).

4.5 Interaction with other medicinal products and other forms of interaction

Buprenorphine should not be administered together with:

• • Alcoholic drinks or medicines containing alcohol, as alcohol increases the sedative effect of

buprenorphine.

Buprenorphine should be used cautiously when co-administered with:

• • Benzodiazepines: This combination may result in death due to respiratory depression of central origin. Therefore, dosages must be limited and this combination must be avoided in cases where there is a risk of misuse. Patients should be warned that it is extremely dangerous to selfadminister non-prescribed benzodiazepines while taking this product, and should also be cautioned to use benzodiazepines concurrently with this product only as directed by their healthcare professional (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 than benzodiazepines, 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 full opioid agonist in patients receiving buprenorphine. Therefore, the potential to overdose with a full agonist exists, especially when attempting to overcome buprenorphine partial agonist effects, or when buprenorphine plasma levels are declining (see section 4.4).
• • Opioid antagonists: naltrexone and nalmefene can block the pharmacological effects of buprenorphine. Co-administration during buprenorphine treatment is contraindicated due to the potentially dangerous interaction that may precipitate a sudden onset of prolonged and intense opioid withdrawal symptoms (see section 4.3).
• • CYP3A4 inhibitors and inducers: Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when Sixmo is given concurrently with medicinal products that affect CYP3A4 activity. CYP3A4 inhibitors may inhibit the metabolism of buprenorphine resulting in increased Cmax and AUC of buprenorphine and norbuprenorphine. Patients treated with CYP inhibitors (e.g. ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, verapamil, diltiazem, amiodarone, amprenavir, fosamprenavir, aprepitant, fluconazole, erythromycin and grapefruit juice) should be monitored for signs and symptoms of toxicity or overdose (miosis, lip cyanosis, sedation, bradycardia, hypotension, respiratory depression). In case toxicity or overdose symptoms are observed, the removal of the implants and transition to a medicinal product that allows dose adjustment are required.
• • Similarly, inducers of CYP3A4 (e.g. phenobarbital, carbamazepine, phenytoin, rifampin) may have the potential to reduce buprenorphine plasma concentrations because of increased metabolism of buprenorphine to norbuprenorphine.
• • Monoamine oxidase inhibitors (MAOI): Possible exacerbation of the effects of opioids, based on experience with morphine.
• • Serotonergic medicinal products, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited data from the use of buprenorphine in pregnant women. Studies in animals have 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 infant even after a short period of administration. Long-term administration of buprenorphine during the last three months of pregnancy may cause a withdrawal syndrome in the neonate (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus or convulsions). The syndrome may be milder and more protracted than that from short acting full g-opioid agonists. The syndrome is generally delayed for several hours to several days after birth. The nature of the syndrome may vary depending upon the mother’s drug use history.

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

Due to the inflexibility with regard to dose increases and to the increased dose requirements during pregnancy, Sixmo is not considered to be an optimal treatment choice for pregnant women, therefore treatment with Sixmo should not be started in pregnant women. Sixmo is not recommended during pregnancy and in women of childbearing potential not using contraception. If pregnancy occurs during treatment 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 this situation.

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

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

Plasma concentrations of buprenorphine after insertion of Sixmo are highest during the first 24 to 48 hours. In particular, patients may experience somnolence for up to one week after subcutaneous insertion; therefore, they should be cautioned about driving or operating hazardous machinery especially during this time period. Before engaging driving or operating hazardous machinery patients should be reasonably certain that Sixmo does not adversely affect their ability to engage in such activities.

4.8 Undesirable effects

Summary of the safety profile

The safety of Sixmo was evaluated in five Phase 3 studies (3 double-blind and placebo and/or active-controlled studies, and two open-label extension studies).

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, constipation and insomnia. These are very common or common adverse reactions with buprenorphine.

Implant site related adverse reactions with the current (and commercially used) insertion and removal techniques were reported in 25.9% and 14.1% of patients in the double-blind and extension studies, respectively. Most frequent implant adverse reactions were implant site pain, implant site pruritus, implant site haematoma, implant site haemorrhage, implant site erythema and implant site rash.

Tabulated list of adverse reactions

Adverse reactions (implant and non-implant) reported are listed in the following table. These adverse reactions are presented by MedDRA system organ 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 be estimated from the available data).

Table 1: Adverse reactions reported in clinical studies and from post-marketing data with

Sixmo and/or re	ported with other buprenorphine product
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 system disorders	uncommon	lymphadenopathy, neutropenia
Metabolism and nutrition disorders	common	decreased appetite
	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 blurred
Cardiac disorders	common	palpitations
	uncommon	atrial flutter, bradycardia
Vascular disorders	common	hot flush, vasodilatation, hypertension
Respiratory, thoracic and mediastinal disorders	common	cough,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 tissue disorders	common	hyperhidrosis
	uncommon	cold sweat, dry skin, rash, skin lesion, ecchymosis*
Musculoskeletal and connective disorders	common	bone pain, 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 breast disorders	uncommon	dysmenorrhoea, erectile dysfunction
General disorders and administration site conditions	common	fatigue, chills, asthenia, pain, implant site haematoma*, implant site pain*, implant site pruritus*, implant site haemorrhage*, implant site erythema*, implant site scar*, chest pain, malaise, drug withdrawal syndrome

System organ class	Frequency	Adverse reactions
	uncommon	oedema peripheral, discomfort, face oedema, feeling cold, pyrexia, swelling, implant site oedema*, implant site reaction*, device expulsion*, impaired healing*, implant site paraesthesia*, implant site rash*, scarring
Investigations	common	alanine aminotransferase increased
	uncommon	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 procedural complications	common	procedural pain, procedural site reaction*
	uncommon	post procedural complication (), contusion (), wound dehiscence*, migration of implanted drug, device 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

Description of selected adverse reactions

Risk of serious complications of insertion and removal of implants

Rare but serious complications including nerve damage and migration resulting in embolism and death may result from improper insertion of drug implants (see section 4.4). In the post-marketing setting, 2 cases were reported where Sixmo implants had locally migrated from the insertion site. In 3 patients treated in clinical studies, and in 1 patient treated during post-marketing, implants or fragments could not be located 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 (breakage associated with an adverse reaction) were observed.

Risk of expulsion

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

Symptoms

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

Treatment

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

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

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

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other nervous system drugs, Drugs used in opioid dependence, ATC code: N07BC01

Mechanism of action

Buprenorphine is an opioid partial agonist/antagonist which binds to the p (mu) and k (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible properties at the p receptors which, over a prolonged period, minimises the need for use of other opioids.

During clinical pharmacologic studies in opioid-dependent patients, buprenorphine shows ceiling effects on a number of PD and safety parameters. It has a relatively wide therapeutic window as a consequence of its partial agonist/antagonist properties, which attenuates suppression of cardiovascular and respiratory function.

Clinical efficacy and safety with Sixmo

The safety and efficacy of Sixmo was investigated in 3 double-blind Phase 3 clinical studies 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. for 2 implant cycles).

The demonstration of efficacy relies primarily on study PRO-814, a randomized, double-blind and active-controlled Phase 3 study in adult patients who met DSM-IV-TR criteria for opioid dependence and who were clinically stabilised on sublingual buprenorphine. In this study, approximately 75% of patients reported prescription opioids as the primary opioid of abuse, and 21% of patients reported heroin as the primary opioid of abuse. The implant time was 24 weeks. This study enrolled 84 patients in 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 sublingual buprenorphine of 8 mg/day or less were transferred to 4 Sixmo implants (and daily sublingual placebo), or sublingual buprenorphine 8 mg/day or less (and 4 placebo implants). The primary endpoint was proportion of responders, defined as patients with no more than 2 of 6 months with evidence of illicit opioid use based on a composite of both urine and self-report results. This endpoint was considered to be of clinical relevance in the targeted indication. Sixmo was shown to be noninferior to sublingual buprenorphine, the proportion of responders being 87.6% in the sublingual buprenorphine 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 in treatment was high, with 96.4% of Sixmo patients and 94.4% of sublingual buprenorphine patients completing the study.

Two additional randomised, double-blind, placebo-controlled Phase 3 studies provide supportive data on efficacy and PK (Studies PRO-805 and PRO-806). In both studies adult patients with opioid dependence who were new entrants to buprenorphine treatment were treated over 24 weeks with 4 Sixmo or 4 placebo implants. Patients not adequately treated with the 4 implant dose could receive a fifth implant. Study PRO-806 included an open-label comparator arm with sublingual buprenorphine (12 to 16 mg/day). Patients in all groups were allowed to use supplemental sublingual buprenorphine 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 N=108	Placebo N=55	Sixmo N=114	Placebo N=54	sublingual buprenorphine N=119
Median age (range), years	33 (19 – 62)	39 (20 – 61)	36 (19 – 60)	33 (19 – 59)	32 (18 – 60)
Primary opioid of abuse, n (%)
Heroin	69 (63.9%)	34 (61.8%)	76 (66.7%)	28 (51.9%)	75 (63.0%)
Prescription opioids	39 (36.1%)	21 (38.2%)	38 (33.3%)	26 (48.1%)	43 (36.1%)

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 the percentage of urine samples that were negative for illicit opioids (as evaluated through thrice weekly urine toxicology and patient self-reported opioid use).

In study PRO-805, the primary endpoint was the CDF of the percentage of urine samples that were negative for illicit opioids over weeks 1 to 16, while the CDF over weeks 17 to 24 was evaluated as secondary 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 N=108	Placebo 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.

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 urine samples that were negative for illicit opioids for Weeks 1 to 24 in the Sixmo and placebo groups (coprimary 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 results	Sixmo N=114	Placebo N=54	Sublingual 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 between treatments (p<0.0001) was seen, which was in favour of Sixmo.

Figure 2: Cumulative Distribution Function of the Percentage of Urine Samples Negative for Opioids in Weeks 1–24 (co-primary endpoint 1), Study PRO-806 (ITT Population)

Percentage of Urine Samples Negative for Opioids in Weeks 1 —24

Treatment         Sixmo Placebo       SL BPN

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 that were negative for opioids over 24 weeks for Sixmo versus sublingual buprenorphine. Despite the use of 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 was very similar to the results in the Sixmo group (33% versus 31%), and non-inferiority of Sixmo to sublingual 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 studies were 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 BPN was 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 completing studies PRO-805 and PRO-806, respectively.

The majority of patients (around 80%) in both studies were adequately treated with 4 implants; around 20% of patients required a dose increase with a fifth implant.

In a subset of patients, Sixmo implants broke during implant removal. Breakage rates decreased in studies using the current technique and training. Generally, breakage was not perceived as a safety concern 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 N= 99	Sixmo N=78	Sixmo N=82
Number (%) of broken implants	71 (17.0%)	81 (25.0%)	35 (10.7%)
Number (%) of patients with broken 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.

Paediatric population

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 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

The Sixmo PK was assessed in opioid-dependent patients treated with Sixmo in studies TTP-400–0201, 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 to severe 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 at 12 hours after insertion. After the initial buprenorphine peak, the plasma buprenorphine concentrations decreased slowly and steady-state plasma buprenorphine concentrations were reached by approximately week 4. Mean steady-state plasma buprenorphine concentrations were consistent across all clinical studies, at approximately 0.5 to 1 ng/mL (with the 4-implant dose), and were maintained for 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 day sublingual buprenorphine.

Plasma buprenorphine concentrations after Sixmo are illustrated in figure 3. Mean plasma buprenorphine 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 pooled data from studies PRO-805, PRO-806, PRO-807 and PRO-811.

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

Distribution

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

Biotransformation

Buprenorphine undergoes N-dealkylation to its major pharmacologically active metabolite norbuprenorphine and subsequent glucuronidation. The formation of norbuprenorphine was initially found to be performed by CYP3A4; subsequent studies also demonstrated the involvement of CYP2C8. Both buprenorphine and norbuprenorphine can further undergo glucuronidation by UDP-glucuronosyltran­sferases.

Elimination

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

Special populations

Hepatic impairment

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 be increased in patients with moderate and severe hepatic impairment.

Sixmo is contraindicated in patients with severe hepatic impairment.

Renal impairment

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

Elderly

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

5.3 Preclinical safety data

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 of buprenorphine.

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 and female fertility. Studies in animals have shown reproductive toxicity.

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

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Ethylene vinyl acetate copolymer

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

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

Implant kit: 4 Sixmo implants with 1 applicator

6.6 Special precautions for disposal

The removed implant contains a significant amount of residual buprenorphine.

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

7. MARKETING AUTHORISATION HOLDER

L. Molteni & C. dei F.lli Alitti Soc.Es.S.p.A,

Strada Statale 67,

50018 Scandicci (Firenze),

Italy

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1369/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20 June 2019