This information is intended for use by health professionals

1. Name of the medicinal product

Dropizol 10 mg/ml oral drops, solution

2. Qualitative and quantitative composition

1 ml of oral liquid contains 1 ml of tincture from Papaver somniferum L., succus siccum (Opium, raw) corresponding to 10 mg of morphine.

1 drop contains 50 mg opium tincture corresponding to 0.5 mg (10 mg/ml) anhydrous morphine

1 ml = 20 drops

Extraction solvent: 33 % ethanol (V/V)

Excipients with known effect: 33 % ethanol (V/V)

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Oral drops, solution

Appearance: dark, reddish brown liquid.

4. Clinical particulars
4.1 Therapeutic indications

Symptomatic treatment of severe diarrhoea in adults, when use of other anti- diarrhoea treatments have not given sufficient effect.

4.2 Posology and method of administration

Posology

Usual starting dose in adults: 5–10 drops, 2–3 times daily.

Individual doses should not exceed 1 ml, and the total daily dose should not exceed 6 ml

The posology should be individualized to use the lowest effective dose for the shortest duration of time taking into account the patient's general condition, the patient's age, weight, and medical history (see sections 4.3 and 4.4).

Paediatric population

Dropizol should not be used in children and adolescents aged below 18 years for safety reasons, see section 5.1.

Treatment should be initiated and supervised by a specialist, i.e. oncologist or gastroenterologist.

Particular caution should be exercised when prescribing this drug due to its morphine content. The treatment period should be as short as possible.

Elderly

Caution should be exercised and the dosage initially reduced in treatment of elderly subjects.

Hepatic impairment

Morphine may precipitate coma in hepatic impairment – avoid or reduce dose. See Sections 4.3 and 4.4.

Renal impairment

Elimination is reduced and delayed in renal impairment - avoid or reduce dose. See Sections 4.3 and 4.4.

Method of administration

Oral use.

The product can be used undiluted or mixed in a glass of water. After mixture with water, it should be used immediately. If the product is used undiluted the correct dosage can be administered with a spoon.

4.3 Contraindications

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

• Opiate dependency.

• Glaucoma.

• Severe hepatic or renal impairment.

• Delirium tremens.

• Severe head trauma.

• Risk of paralytic ileus.

• Chronic obstructive pulmonary disease

• Acute asthma

• Severe respiratory depression with hypoxia and/or hypercapnia

• Heart failure secondary to lung disease (Cor pulmonale)

4.4 Special warnings and precautions for use

Dropizol should only be used following investigations of the etiology causing the symptoms and when first-line treatment has not given adequate results.

Dropizol drops should be used with caution in the following conditions / for the following patients

• The elderly

• Chronic renal disease and/or hepatic disease.

• Alcoholism.

• Biliary colic, cholelithiasis, biliary duct diseases

• Head injuries or increased intracranial pressure

• Reduced consciousness

• Cardiorespiratory shock

• Monoamine oxidase inhibitors (including moclobemide), or within two weeks of their withdrawal

• Adrenocortical deficiency

• Hypothyroidism

• Low blood pressure with hypovolaemia

• Pancreatitis

• Prostatic hyperplasia and other conditions predisposing to urinary retention

• Concomitant administration of other antidiarrheal or antiperistaltic drugs, anticholinergics, antihypertensives

• Convulsive disorders

• Gastrointestinal haemorrhage

A health care professional should be contacted in case of difficulty to urinate.

Adjustment of dose may be needed in the elderly, patients with thyroid insufficiency, and patients with mild to moderate renal or hepatic impairment (see also section 4.2 and 4.3).

Avoid use in older adults with a history of falls or fractures as ataxia, impaired psychomotor function, syncope, and additional falls may occur. If use is necessary, consider reducing use of other CNS-active agents that increase risk of falls and fractures and implement other strategies to reduce risk of falls.

Anti-diarrheals inhibiting peristalsis should be used with caution in patients with infection or inflammatory bowel diseases due to the increased risk of absorption of toxins, and of developing toxic megacolon and intestinal perforation. Due to the risk of paralytic ileus, Dropizol is not recommended before a surgical operation or within 24 hours after operation. If paralytic ileus is suspected during the use of Dropizol, the treatment must be stopped immediately.

Repeated administration may cause dependence and tolerance and the use of opium may lead to addiction to the substance. Particular caution should be exercised in individuals predisposed to addiction to narcotics and alcohol.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

Concomitant use of Dropizol and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death.

Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Dropizol concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Administer at reduced doses and with the utmost caution to patients who are also being treated with other narcotic agents, sedatives, and tricyclic antidepressants and MAO-inhibitors (see also section 4.2).

Should only be used with caution in patients in high-risk groups, such as patients with epilepsy and hepatic disease.

Opioids may inhibit the hypothalamic–pituitary–adrenal (HPA) or gonadal axis at multiple levels and is most pronounced after long term use.

This may lead to symptoms of adrenal insufficiency.

This medicinal product contains 33 vol % ethanol (alcohol), i.e. up to 260 mg per dose, equivalent to 6.6 ml beer or 2.8 ml wine.

4.5 Interaction with other medicinal products and other forms of interaction

The risk of sedation, respiratory depression, coma or death increases because of additive CNS depressant effect by ethanol, hypnotics (e.g. zolpidem), general anaesthetics (e.g. barbiturates), MAO inhibitors (e.g. safinamide), tricyclic antidepressants and psychotropic drugs with a sedative action (e.g. phenothiazines), gabapentin, antiemetic medications (e.g. bromopride, meclizine, metoclopramide), antihistamines (e.g. carbinoxamine, doxylamine), and other opioids (e.g. alfentanil, butorphanol, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, oxycodone, oxymorphone, remifentanil, sufentanil, tapentadol, tramadol). The dose and duration of concomitant use should be limited (see section 4.4). Dropizol should not be used with other morphine agonists/antagonists (buprenorphine, nalbuphine, nalmefene, naltrexone, pentazocine) because of their competitive receptor- binding that may aggravate withdrawal symptoms and reduce therapeutic effect

Due to the ethanol content, Dropizol should not be used concomitantly with disulfiram or metronidazole. Both of these drugs can cause disulfiram-like reactions (flushing, rapid breathing, tachycardia).

Rifampicin induces CYP 3A4 in the liver thus increasing the metabolism of morphine, codeine and methadone. The effect of these opioids is thereby decreased or counteracted.

Concurrent administration of morphine and antihypertensive drugs may increase the hypotensive effects of antihypertensive agents or other drugs with hypotensive effects.

Morphine inhibits the glucuronidation of zidovudine in vitro.

Morphine's duration of action may be reduced after taking fluoxetine.

Cimetidine and ranitidine do not affect the bioavailability of opium, oral drops.

Other drug-drug interactions

Amphetamine and analogues can reduce the sedative effect of opioids. Loxapine and periciazine can increase the sedative effect of opioids. Concomitant use of flibanserin and opioids may increase the risk of CNS depression. Opioids can increase the plasma concentrations of desmopressin and sertraline.

Ethanol, see Section see 4.4.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is limited amount of data from the use of opium in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Dropizol is not recommended during pregnancy unless the benefits clearly outweigh the risks to both mother and child.

When morphine is used during pregnancy up to partition, neonatal withdrawal syndrome can occur.

Breastfeeding

Opium is excreted in human milk, where it reaches higher concentrations than in maternal plasma. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Dropizol therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. If Dropizol is used during breastfeeding, infants should be closely monitored for symptoms of respiratory depression and sedation.

Fertility

There are insufficient data to assess human risk to fertility. Animal studies have shown chromosomal damage in reproductive cells (see section 5.3). Men and women of reproductive age should take necessary precautions.

4.7 Effects on ability to drive and use machines

Due to its undesirable effects, Dropizol may have a major influence on the ability to drive and use machines.

4.8 Undesirable effects

The adverse events reported for Dropizol drops are derived from literature and post- marketing experience with other morphine products.

Endocrine disorders

Very rare /<1/10,000)

Syndrome of inadequate ADH-secretion (SIADH), Amenorrhoea

Not known (cannot be estimated from the available data)

Adrenal insufficiency

Psychiatric disorders

Not known (cannot be estimated from the available data)

Addiction, dysphoric mood, restlessness, decreased libido or potency, hallucinations.

Nervous system disorders

Very common (≥1/10)

Common (≥1/100 to <1/10)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Drowsiness

Dizziness, headache

Muscle cramps, seizures, allodynia and hyperalgesia

Euphoria

Eye disorders

Common (≥1/100 to <1/10)

Very rare (<1/10,000)

Miosis

Blurred vision, diplopia, nystagmus

Cardiac disorders

Uncommon (≥1/1,000 to <1/100)

Tachycardia, bradycardia, palpitations, facial flushing

Vascular disorders

Rare (≥1/10,000 to <1/1,000)

Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Very rare /<1/10,000)

Bronchospasms, cough decreased

Respiratory depression

Dyspnoea

Gastrointestinal disorders

Very common (≥1/10)

Common (≥1/100 to <1/10)

Rare ( ≥1/10,000 to <1/1,000)

Very rare /<1/10,000)

Constipation, dry mouth

Nausea, vomiting, loss of appetite, dyspepsia, dysgeusia

Pancreatic enzymes increase and pancreatitis

Ileus, abdominal pain

Hepatobiliary disorder

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Hepatic enzymes increased

Biliary colic

Skin and subcutaneous tissue disorders

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Very rare /<1/10,000)

Urticaria, sweating

Pruritus

Exanthema, peripheral oedema

Musculoskeletal and connective tissue disorders

Not known (cannot be estimated from the available data)

Involuntary muscle contractions

Renal and urinary disorders

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare ( ≥1/10,000 to <1/1,000)

Urinary retention

Urethral spasm

Renal colic

General disorders and administration site conditions

Common (≥1/100 to <1/10)

Rare (≥1/10,000 to <1/1,000)

Very rare /<1/10,000)

Not known (cannot be estimated from the available data)

Asthenia

Withdrawal symptoms

Feeling unwell, shivering

Hyperthermia, vertigo

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

Morphine toxicity. Lethal doses are primarily determined by the morphine content.

Symptoms of overdose

Miosis, respiratory depression, somnolence, reduced skeletal muscle tone and drop in blood pressure. In severe cases circulatory collapse, stupor, coma, bradycardia and non- cardiogenic lung oedema, hypotension and death may occur; abuse of high doses of strong opioids such as oxycodone can be fatal.

Therapy of overdose

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.

In the event of overdosing intravenous administration of an opiate antagonist may be indicated.

Furthermore, gastric lavage can be taken into consideration.

Supportive treatment (artificial respiration, oxygen supply, administration of vasopressors and infusion therapy) should, if necessary, be applied in the treatment of accompanying circulatory shock.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ATC code: A 07 DA 02. Antipropulsives.

Opium alkaloids (opioids and isoquinoline derivatives) induce constipation, euphoria, analgesia and sedation dependent on the dose and derivative.

These effects of are mediated by opioid receptors. The receptors are widely distributed in the central nervous system. Receptors are also present to a lesser extent, in vas deferens, knee joints, the gastrointestinal tract, and in the heart and the immune system.

Opioid peptides modify the gastrointestinal (GI) function by interaction with opioid receptors on the enteric circuitries that control motility and secretion. Opioid receptors have been localized in the GI tract of humans, but their relative distribution varies with GI layer and GI region1.

The μ-opioid receptor agonists inhibit gastric emptying, increases pyloric muscle tone, induce pyloric and duodenojejunal phasic pressure activity, disturb the migrating myoelectric complex, delay transit time through the small and large intestine and elevate the resting anal sphincter pressure. In addition to this, opioids attenuate the intestinal secretion of electrolytes and water and thereby facilitate the net absorption of fluid. In addiction to this, the μ, κ and δ-opioid receptors contribute to opioid-inhibition of muscle activity in the intestine. The result of all these effects is constipation.

The use of opium is well-established for treatment of diarrhoea in the clinic. Controlled clinical studies is not available.

No clinical trials in the paediatric population have been performed and the product is not considered suitable in this population because of safety concerns, see section 4.2.

5.2 Pharmacokinetic properties

Absorption

Peak serum concentrations of morphine, the main alkaloid of the opium extract, are achieved within 2 to 4 hours after oral administration.

Distribution

After absorption, morphine is bound to plasma proteins in the proportion of 30 %.

Biotransformation

Opium alkaloids are extensively metabolized to glucuronide conjugates (3-glucuronide (M3G) and 6-glucuronide (M6G)) that undergo an enterohepatic cycle. 6-glucuronide is a metabolite of morphine about 50 times more active than the parent substance.

Morphine is also demethylated, which leads to another active metabolite, normorphine.

Codeine is metabolized to give codeine-6-glucuronide, morphine (the only active metabolite) and norcodeine. Since codeine is present in opium extract at levels ten times lower than those of morphine, its hepatic transformation has little effect on the overall bioavailability of morphine.

Elimination

The elimination half-life of morphine is approximately 2 hours. An elimination half-life of 2.4 to 6.7 hours has been reported for M3G. About 90 % of total morphine is excreted in 24 hours with traces in urine for 48 hours or more 9.

The elimination of glucuronoconjugate derivatives is essentially by the urinary route, both by glomerular filtration and tubular secretion. Faecal elimination is low (<10 %).

5.3 Preclinical safety data

Several studies have shown that morphine induces chromosome damage in animals in somatic and germ cells and in human somatic cells. A genotoxic potential for humans is therefore expected. Long-term animal studies on the carcinogenic potential of morphine have not been conducted.

Studies have indicated an association between regular use of opium and increased risk of gastric adenocarcinoma and cancers in the oesophagus, larynx, bladder and lung.

The mechanism of this association is not fully understood.

Animal studies have shown reproductive toxicity during the whole pregnancy (CNS malformations, foetal growth retardation, skeleton defects, testis atrophy, changes in neurotransmitter systems and behaviour, dependency) as well as impairment of sexual behaviour in male and fertility in female animals, see section 4.6.

The relevance to clinical use is not known.

6. Pharmaceutical particulars
6.1 List of excipients

Ethanol 96% v/v

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months.

4 weeks after the bottle has been opened (in-use stability)

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

Brown glass bottle with a white LDPE dropper and white polypropylene (PP) childproof closure. Pack sizes of 1 x 10 ml, 2 x 10 ml, 3 x 10 ml, 4 x 10 ml, 5 x 10 ml and 10 x 10 ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

7. Marketing authorisation holder

Pharmanovia A/S

Jægersborg Allé 164

DK-2820 Gentofte

Denmark

Tel: +45 3333 7633

Fax: +45 3332 3107

e-mail: [email protected]

8. Marketing authorisation number(s)

PL 41284/0003

9. Date of first authorisation/renewal of the authorisation

14/09/2017

10. Date of revision of the text

31/03/2020