SIXMO Implant Ref.[28026] Active ingredients: Buprenorphine

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 µ (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).

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 C_max 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).

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 μ-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).

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.

Summary of the safety profile

The safety of Sixmo was evaluated in five Phase 3 studies (3 double-blind and placebo and/or activecontrolled 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 reported with other buprenorphine product:

^* 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 Appendix V.

Not applicable.