Zubsolv

Package leaflet: Information for the patient

Zubsolv 0.7 mg/0.18 mg sublingual tablets, 1.4 mg/0.36 mg sublingual tablets, 2.9 mg/0.71 mg sublingual tablets, 5.7 mg/1.4 mg sublingual tablets, 8.6 mg/2.1 mg sublingual tablets, 11.4 mg/2.9 mg sublingual tablets

Buprenorphine/naloxone
Please read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet

1. What Zubsolv is and what it is used for
2. What you need to know before taking Zubsolv
3. How to take Zubsolv
4. Possible side effects
5. How to store Zubsolv
6. Contents of the pack and other information

1. What Zubsolv is and what it is used for

Zubsolv contains the active substances buprenorphine and naloxone. Zubsolv is used to treat opioid dependence (narcotic drugs) such as heroin or morphine in individuals with drug dependence who have agreed to undergo treatment for their addiction. Zubsolv is used in adults and adolescents over the age of 15 who are also receiving medical, social, and psychological support.

How Zubsolv works
The tablet contains buprenorphine, which is responsible for treating opioid dependence (narcotic drugs). It also contains naloxone, which is included to discourage intravenous abuse of the product.

2. What you need to know before taking Zubsolv

Do not take Zubsolv if you:

• are allergic to buprenorphine, naloxone, or any of the other ingredients of this medicine (listed in section 6).
• have severe breathing problems
• have severe liver problems
• are intoxicated due to alcohol or are experiencing tremors, sweating, anxiety, confusion, or hallucinations caused by alcohol
• are taking naltrexone or nalmefene for the treatment of alcohol abuse or opioid dependence.

Warnings and precautions

• Misuse, abuse, and diversion Severe, potentially fatal infections may occur if Zubsolv is misused by intravenous administration. This medicine may be targeted by individuals who abuse prescription drugs and should be stored securely to protect against theft. Do not give this medicine to anyone else (see section 5). It may cause death or otherwise be dangerous to them.
• Breathing problems (see also 'Do not take Zubsolv if' above) Some people have died from respiratory failure (inability to breathe) due to misuse of this medicine or because they took it in combination with other central nervous system depressants such as alcohol, benzodiazepines (tranquilizers), or other opioids.

This medicine should be used with caution in patients with asthma or respiratory insufficiency.
This medicine may cause severe, potentially fatal respiratory depression (reduced ability to breathe) in children and in individuals who are not opioid-dependent if taken accidentally or deliberately.

• Drowsiness This medicine may cause drowsiness, especially when taken together with alcohol or other central nervous system depressants (such as tranquilizers, sedatives, or hypnotics).
• Dependence This product may cause dependence.
• Liver damage Liver damage has been reported after taking buprenorphine/naloxone, particularly when the medicine is misused. This may also be due to viral infections (chronic hepatitis C), alcohol abuse, anorexia, or use of other medicines that may damage the liver (see section 4). Your doctor may periodically perform blood tests to monitor your liver function. Inform your doctor if you have any liver problems before starting treatment with Zubsolv.
• Withdrawal symptoms This product may cause withdrawal symptoms if you take it less than 6 hours after using a short-acting opioid (e.g., morphine, heroin) or less than 24 hours after using a long-acting opioid such as methadone.

Zubsolv may also cause withdrawal symptoms if you stop taking the medicine suddenly.

• Blood pressure This product may cause a sudden drop in your blood pressure, leading to dizziness when you stand up quickly from a lying position.
• Sleep-related breathing disorders

Zubsolv may cause sleep-related breathing disorders such as sleep apnea (breathing pauses during sleep) and sleep-related hypoxemia (low blood oxygen levels during sleep). Symptoms may include breathing pauses during sleep, nighttime awakenings due to shortness of breath, difficulty maintaining sleep, or excessive daytime sleepiness. If you or someone else observes these symptoms, contact your doctor. Your doctor may consider reducing your dose.

• Children and adolescents You may be monitored more closely by your doctor if you are under 18 years of age. This medicine must not be taken by individuals under 15 years of age.

• Diagnosis of unrelated medical conditions This medicine may mask pain symptoms, which could delay the diagnosis of certain diseases. Do not forget to inform your doctor that you are taking this medicine.

Talk to your doctor before taking Zubsolv if you:

• suffer from depression or other conditions treated with antidepressants. Taking these medicines together with Zubsolv may lead to serotonin syndrome, a potentially life-threatening condition (see “Other medicines and Zubsolv”)
• have kidney problems
• have recently suffered a head injury or have a brain disorder
• have low blood pressure, an enlarged prostate gland, or difficulty passing urine due to urethral narrowing
• have an underactive thyroid gland, which may cause fatigue or weight gain
• have impaired adrenal gland function (e.g., Addison's disease)
• have problems with the biliary tract (e.g., gallbladder, bile duct)
• are elderly
• are debilitated

Other medicines and Zubsolv
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
Some medicines may increase the side effects of Zubsolv and may sometimes cause very serious reactions. Do not take any other medicines while taking Zubsolv without first discussing it with your doctor, especially:

• antidepressants such as moclobemide, tranylcypromine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, duloxetine, venlafaxine, amitriptyline, doxepin, or trimipramine. These medicines may interact with Zubsolv and cause symptoms such as involuntary rhythmic muscle contractions, including those controlling eye movements, agitation, hallucinations, coma, excessive sweating, tremor, exaggerated reflexes, increased muscle contraction, and fever above 38°C. Contact your doctor if you experience these symptoms.
• Naltrexone and nalmefene (medicines used to treat addiction disorders), as these may block the therapeutic effects of Zubsolv. They should not be taken at the same time as Zubsolv, as this may cause a sudden onset of prolonged and severe withdrawal symptoms.
• Benzodiazepines (used to treat anxiety or sleep disorders), such as diazepam, temazepam, alprazolam. Concomitant use of Zubsolv with sedative medicines such as benzodiazepines or related drugs increases the risk of drowsiness, breathing difficulties (respiratory depression), coma, and may be fatal. Therefore, concomitant use should only be considered when no other treatment options are available. However, if your doctor prescribes Zubsolv together with sedative medicines, the dose and duration of concomitant treatment must be limited. Inform your doctor about all sedative medicines you are taking and follow their dosage recommendations carefully. It may be helpful to inform friends or family members to watch for the signs and symptoms listed above. Contact your doctor if such symptoms occur.
• Gabapentin or pregabalin for treating epilepsy or nerve-related pain (neuropathic pain).
• Other medicines that may make you feel drowsy, used to treat conditions such as anxiety, insomnia, seizures/epileptic fits, pain, and other mental disorders. These types of medicines may reduce alertness, making it dangerous for you to drive or operate machinery. They may also cause central nervous system depression, which is very serious. Below is a list of examples of these types of medicines:
  • other opioid-containing medicines, such as methadone, certain painkillers, and cough suppressants
• some antidepressants (used to treat depression) such as isocarboxazid, phenelzine, selegiline, tranylcypromine, valproate, and MAO inhibitors, which may increase the effects of this medicine
• H1-receptor antagonist sedatives (used to treat allergic reactions) such as diphenhydramine and chlorphenamine
• barbiturates (used to induce sleep or sedation) such as phenobarbital, secobarbital
• tranquilizers (used to induce sleep or sedation) such as chloral hydrate
• clonidine (used to treat high blood pressure) and related medicines may prolong the effects of this medicine
  • antiretrovirals (used to treat HIV) such as ritonavir, nelfinavir, indinavir may increase the effects of this medicine
  • some antifungal agents (used to treat fungal infections), such as ketoconazole, itraconazole, and some antibiotics, may enhance the effects of this medicine
  • Some medicines may reduce the effect of Zubsolv. These include medicines used to treat epilepsy (such as carbamazepine and phenytoin) and medicines used to treat tuberculosis (rifampicin)

Zubsolv with food, drinks, and alcohol
Alcohol may increase drowsiness and the risk of respiratory failure when taken with Zubsolv.
Do not take Zubsolv with alcohol. Do not swallow or consume any food or drink until the tablet is completely dissolved.

Pregnancy and breastfeeding
The risks associated with using Zubsolv in pregnant women are not known. Inform your doctor if you are pregnant or planning a pregnancy. Your doctor will decide whether treatment should continue with an alternative medicine.
If taken during pregnancy, particularly in late pregnancy, medicines like Zubsolv may cause withdrawal symptoms in the newborn, including breathing problems. These may appear several days after birth.
Do not breastfeed while taking this medicine, as Zubsolv passes into breast milk.
Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines
Zubsolv may cause drowsiness, dizziness, or disturbances in thinking. This may occur more frequently during the first weeks of treatment when your dose is adjusted, but may also occur if you drink alcohol or take other sedative medicines while on Zubsolv. Do not drive, operate tools or machinery, or perform hazardous activities until you know how this medicine affects you.

Zubsolv contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially ‘sodium-free’.

3. How to take Zubsolv

Take this medicine exactly as directed by your doctor or pharmacist. If you have
any doubts, consult your doctor or pharmacist.
Your treatment has been prescribed and monitored by doctors experienced in treating
drug dependence.
Your doctor will determine the best dose for you. During treatment, your doctor may adjust the
dose, depending on your response.

Initial treatment
The recommended starting dose for adults and adolescents over 15 years of age is:

• one Zubsolv 1.4 mg/0.36 mg tablet per day, or
• one Zubsolv 2.9 mg/0.71 mg tablet per day

An additional tablet of Zubsolv 1.4 mg/0.36 mg or 2.9 mg/0.71 mg may be
administered on day 1, depending on need.
Other strengths are available, and your doctor will decide the optimal treatment for you. This
may involve taking a combination of different strengths; however, your daily dose must not exceed 17.2 mg of buprenorphine.
Clear and definite signs of withdrawal must be present before taking your first dose of Zubsolv. Your doctor’s assessment of your readiness for treatment will guide the timing of your first Zubsolv dose.

• Starting Zubsolv treatment during heroin dependence: If you are dependent on heroin or a short-acting opioid, your first dose of Zubsolv should be taken when signs of withdrawal appear, but not less than 6 hours after the last intake of opioids.
• Starting Zubsolv treatment during methadone dependence: If you have been taking methadone or a long-acting opioid, the methadone dose should ideally be reduced to less than 30 mg/day before starting Zubsolv therapy. The first dose of Zubsolv should be taken when signs of withdrawal appear, but not less than 24 hours after the last dose of methadone.

How to take Zubsolv

• Take your dose once daily or as directed by your doctor.
• Remove the tablet as described below. Open the blister pack only immediately before taking the dose. Never remove the tablet from the blister pack in advance, as the tablet is sensitive to moisture.
• Place the tablets under the tongue.
• Keep the tablets under the tongue until they are completely dissolved.
• Do not chew or swallow the tablets, as the medicine will not work and you may experience withdrawal symptoms.
• Do not eat or drink anything until the tablets are completely dissolved. Although most tablets dissolve within about 40 seconds, it may take 5 to 10 minutes for the tablet to fully dissolve in the mouth.

How to remove the tablet from the blister pack

1. Do not push the tablet through the aluminium foil.

2. Remove only one section from the blister pack by cutting along the dotted line.

3. Fold the pack along the dotted line.

4. Cut in the direction of the arrow. If the blister is damaged, discard the tablet.

Dose adjustment and maintenance therapy
Your doctor may increase the dose of Zubsolv according to your needs. If you feel that the effect of Zubsolv is too strong or too weak, consult your doctor or pharmacist. The maximum daily dose is 17.2 mg.
After a period of effective treatment, you may agree with your doctor to gradually reduce the dose to a lower maintenance level.

Stopping treatment
Do not change your treatment in any way or stop treatment without your doctor’s consent.
Depending on your condition, the dose of Zubsolv may continue to be reduced under close
medical supervision until it can be discontinued.

If you take more Zubsolv than you should
If you or someone else takes an excessive amount of this medicine, you must go to or be taken immediately to an emergency room for treatment, as overdose with Zubsolv can cause serious and potentially fatal breathing problems.
Symptoms of overdose may include breathing that is slower and weaker than normal, increased drowsiness, pinpoint pupils, low blood pressure, feeling unwell, vomiting and/or slurred speech.

If you forget to take Zubsolv
Inform your doctor immediately as soon as possible if you miss a dose.

If you stop taking Zubsolv
Do not change your treatment in any way or stop treatment without the consent of your doctor. Sudden discontinuation of treatment may cause withdrawal symptoms.
If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Contact your doctor immediately or seek urgent medical care if you experience serious side effects such as:

• swelling of the face, lips, tongue or throat which may cause difficulty swallowing or breathing, severe hives/erythema. These may be signs of a severe allergic reaction
• drowsiness and lack of coordination, blurred vision, slurred speech, inability to think well or clearly, or breathing that becomes much slower than normal
• severe tiredness, itching, with yellowing of the skin or eyes. These may be symptoms of liver damage
• seeing or hearing things that are not there (hallucinations)

Other side effects
Very common side effects (may affect more than 1 in 10 patients):

• insomnia (inability to sleep)
• headache
• constipation, nausea
• excessive sweating
• drug withdrawal syndrome

Common side effects (may affect up to 1 in 10 patients):

• flu-like symptoms, infection, sore throat and pain when swallowing, runny nose
• anxiety, depression, decreased sexual desire, nervousness, abnormal thinking
• migraine, dizziness, fainting, increased muscle tension, tingling, drowsiness
• increased tear production (eye watering) or other tear disturbances, blurred vision
• increased blood pressure, hot flushes
• increased cough
• abdominal pain, stomach problems or other stomach disturbances, diarrhoea, flatulence, vomiting
• skin rash, itching, hives
• back pain, joint pain, muscle pain, leg cramps (muscle spasm)
• abnormalities in urine
• difficulty achieving or maintaining erection
• weakness, chest pain, chills, fever, general malaise, pain, swelling (hands and feet)
• abnormal liver function, weight loss
• accidental injuries due to loss of alertness or coordination

Uncommon side effects (may affect up to 1 in 100 patients):

• abnormal blood test results, swollen adrenal glands (lymph nodes)
• abnormal dreams, restlessness, loss of interest, depersonalisation (feeling detached from oneself), drug dependence, exaggerated feeling of well-being, feelings of hostility
• amnesia (memory disturbances), seizures (convulsive fits), speech disorders, tremors
• eye inflammation or infection, decreased pupil size
• fast or slow heartbeat, myocardial infarction (heart attack), palpitations, feeling of chest tightness
• low blood pressure
• asthma, shortness of breath, yawning
• pain and development of sores in the mouth, discolouration of the tongue
• acne, hair loss, dryness or peeling of the skin, skin nodule
• joint inflammation
• protein in the urine, urinary tract infection, difficulty urinating, painful or difficult urination, blood in the urine, kidney stones
• menstrual or vaginal problems, abnormal ejaculation
• sensitivity to heat or cold
• stroke
• excessive muscle activity
• loss of appetite

Not known (frequency cannot be estimated from the available data):

• slow or difficult breathing
• liver damage with or without jaundice
• Dental caries
• hallucinations
• swelling of the face and throat or life-threatening allergic reactions
• drop in blood pressure when moving from sitting or lying down to standing up
• sudden withdrawal syndrome caused by taking the product too soon after using illegal opioids
• drug withdrawal syndrome in newborns

Improper use of this medicine by injection may cause withdrawal symptoms, infections, other skin reactions and potentially serious liver problems (see section 2, Warnings and precautions).
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at the website of the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Zubsolv

Keep this medicine out of the sight and reach of children.
It may cause serious harm and be fatal to individuals who may accidentally or intentionally take this
medicine when it has not been prescribed for them.
Do not use this medicine after the expiry date stated on the carton and blister after Exp. The expiry date refers to the last day of that month.
Store below 25°C.
Store in the original packaging to protect the medicine from moisture.
Zubsolv may be a target for individuals who abuse prescription medicines. Keep this medicine in a safe place to protect it from theft.
Store the blister pack securely.
Do not open the blister pack in advance.
Do not take this medicine in front of children.
An emergency service must be contacted immediately in case of accidental ingestion or suspected ingestion.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Pack contents and other information

What Zubsolv contains
The active substances are buprenorphine and naloxone.
Each 0.7 mg/0.18 mg sublingual tablet contains 0.7 mg of buprenorphine (as hydrochloride) and
0.18 mg of naloxone (as dihydrate hydrochloride).
Each 1.4 mg/0.36 mg sublingual tablet contains 1.4 mg of buprenorphine (as hydrochloride) and
0.36 mg of naloxone (as dihydrate hydrochloride).
Each 2.9 mg/0.71 mg sublingual tablet contains 2.9 mg of buprenorphine (as hydrochloride) and
0.71 mg of naloxone (as dihydrate hydrochloride).
Each 5.7 mg/1.4 mg sublingual tablet contains 5.7 mg of buprenorphine (as hydrochloride) and
1.4 mg of naloxone (as dihydrate hydrochloride).
Each 8.6 mg/2.1 mg sublingual tablet contains 8.6 mg of buprenorphine (as hydrochloride) and
2.1 mg of naloxone (as dihydrate hydrochloride).
Each 11.4 mg/2.9 mg sublingual tablet contains 11.4 mg of buprenorphine (as hydrochloride) and
2.9 mg of naloxone (as dihydrate hydrochloride).
The other excipients are mannitol, citric acid, sodium citrate, microcrystalline cellulose, sodium
croscarmellose, sucralose, levomenthol, colloidal silicon dioxide, and sodium stearyl fumarate. (see section 2 "Zubsolv contains sodium").

Description of the appearance of Zubsolv and pack contents
Zubsolv is available in six different strengths, differing in shape and engraved mark:

Strength of Zubsolv tablet (buprenorphine/naloxone)	Description of Zubsolv tablet	Marking imprinted on Zubsolv tablet	Appearance
0.7 mg/0.18 mg	white to off-white oval tablet, 6.8 mm in length and	".7" on one side
1.4 mg/0.36 mg	white to off-white triangular tablet, 7.2 mm base and 6.9 mm height	"1.4" on one side
2.9 mg/0.71 mg	white to off-white D-shaped tablet, 7.3 mm in height and	"2.9" on one side
5.7 mg / 1.4 mg	white to off-white round tablet, 7 mm in diameter	"5.7" on one side
8.6 mg / 2.1 mg	white to off-white diamond-shaped tablet, 9.5 mm in length and 7 mm in width	"8.6" on one side
11.4 mg/2.9 mg	white to off-white capsule-shaped tablet, 10.3 mm in length and width	"11.4" on one side

Zubsolv is available in blisters of 7, 28, or 30 sublingual tablets.
Not all pack sizes may be marketed.
Marketing Authorization Holder
Accord Healthcare S.L.U.
World Trade Center, Moll de Barcelona s/n
Edifici Est, 6a planta
08039 Barcelona
Spain
Manufacturer
Orexo AB
Virdings allé 32 A
Uppsala 754 50
Sweden
More detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu.
ANNEX IV
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE
VARIATION TO THE TERMS OF THE MARKETING
AUTHORISATIONS
Scientific conclusions
Taking into account the assessment by the Committee for Risk Evaluation in Pharmacovigilance (Pharmacovigilance and Risk Assessment Committee, PRAC) of the Periodic Safety Update Reports (PSURs) for buprenorphine/naloxone, the PRAC's scientific conclusions are as follows:

In view of the available data from the literature on the interaction between opioids and gabapentinoids, supported by a plausible mechanism of action and considering existing warnings included in the product information for other opioid-containing medicines, the PRAC considers that a causal relationship between buprenorphine/naloxone and an interaction with gabapentinoids is at least a reasonable possibility. The PRAC concluded that the product information for medicines containing buprenorphine/naloxone should be amended accordingly.

In view of the available data from the literature on dental caries and spontaneous reports, including in some cases a close temporal relationship, and supported by a plausible mechanism of action, the PRAC considers that a causal relationship between buprenorphine/naloxone and dental caries is at least a reasonable possibility. The PRAC concluded that the product information for medicines containing buprenorphine/naloxone should be amended accordingly.

In view of the available data from the literature on paediatric poisoning and fatal outcomes, spontaneous reports, and supported by a plausible mechanism of action, the PRAC considers that a causal relationship between buprenorphine/naloxone and paediatric poisoning with fatal outcomes is at least a reasonable possibility. The PRAC concluded that the package leaflet for medicines containing buprenorphine/naloxone should be amended accordingly.

Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the overall conclusions and the reasoning provided in the recommendation.

Grounds for the variation to the terms of the marketing authorisations
Based on the scientific conclusions regarding buprenorphine/naloxone, the CHMP considers that the benefit-risk balance of medicines containing buprenorphine/naloxone remains favourable, subject to the proposed amendments to the product information.
The CHMP recommends a variation to the terms of the marketing authorisations.