MEDICAL INFORMATION. NanaBis Cannabis Oil Extract (delta-9-tetrahydrocannabinol and cannabidiol) for oro-buccal administration.

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1 MEDICAL INFORMATION NanaBis Cannabis Oil Extract (delta-9-tetrahydrocannabinol and cannabidiol) for oro-buccal administration. Picture provided for physical product identification Page 1 of 9 Version 1.0

2 MEDICAL INFORMATION NanaBis Cannabis Oil Extract (delta-9-tetrahydrocannabinol and cannabidiol) in a submicron delivery platform for oro-buccal administration. NanaBis is a NON ARTG product which is in clinical trial and available under the Approved Prescriber Scheme (APS) and Special Access Scheme (SAS) DESCRIPTION The drug substance is a 1:1 mixture of two distinct cannabis extracts produced from cultivated Cannabis sativa L. and Cannabis indica L. plants. The plants have been specifically cultivated to produce chemotypes, expressing their cannabinoid content as high delta-9-tetrahydrocannabinol (THC) or high cannabidiol (CBD) chemotypes. NanaBis is provided as a dark-amber liquid in a white 15 ml plastic spray vial and a pump for use as an oro-buccal spray only. The pump is protected with a plastic cap. Active ingredient: Cannabis oil extract (delta-9-tetrahydrocannabinol and cannabidiol) Each 1mL NanaBis oro-buccal spray contains: 8.33 mg delta-9-tetrahydrocannabinol (THC) and 8.33 mg cannabidiol (CBD) and lesser amounts of other cannabinoids (1.3 mg total other cannabinoids). Each 150 microlitre spray contains 1.25 mg THC and 1.25 mg CBD. Each 150 microlitre spray also contains up to mg potassium sorbate. NanaBis contains hydrogenated castor oil, glycerol, peppermint oil, anhydrous citric acid, potassium sorbate, and stevia as inactive ingredients. The molecular formula of THC is C21H30O2, its molecular weight is , and the assigned CAS Number is The molecular formula of CBD is C21H30O2, its molecular weight is and the assigned CAS Number is The chemical structures of THC and CBD are shown below: Page 2 of 9 Version 1.0

3 PHARMACOLOGY Pharmacodynamic Properties Pharmacotherapeutic group: Other Analgesics and Antipyretics ATC Code: N02BG10 Mechanism of Action and Pharmacodynamic Effects There are at least two types of cannabinoid (CB) receptors as part of the human endocannabinoid system. CB1 is found mainly in nerve terminals in the CNS where it modulates neurotransmitter release, and CB2 is found primarily in cells of the immune system. THC, the main psychotropic constituent of cannabis, acts as a partial agonist at both, CB1 and CB2 receptors. Pharmacokinetics Absorption: Information regarding absorption is currently being investigated through clinical trial. For further information, please contact Prof Luis Vitetta (luis_vitetta@medlab.co). Distribution: Cannabinoids are highly lipophilic. The resultant concentrations in the blood following oro-buccal administration of NanaBis are lower than those obtained by inhaling the same dose of THC because absorption is slower and redistribution into fatty tissues is rapid. Additionally, some of the THC undergoes hepatic first pass metabolism to 11-OH-THC, the primary metabolite of THC, and CBD similarly to 7-OH-CBD. Protein binding of THC is high (~97%). THC and CBD may be stored for as long as four weeks in the fatty tissues from which they are slowly released at sub-therapeutic levels back into the blood stream, then metabolised and excreted via the urine and faeces. Metabolism: THC and CBD are metabolised in the liver, and approximately one third of the parent drugs and their metabolites are excreted in the urine (the remainder via the faeces). Several THC metabolites may be psychoactive. Human hepatic P450 2C9 isozyme catalyses the formation of 11-OH-THC, the primary metabolite, which is further metabolised by the liver to other compounds including 11-nor-carboxy- D9-THC (THC-COOH), the most abundant metabolite in human plasma and urine. The P450-3A subfamily catalyses the formation of other hydroxylated minor metabolites. CBD is extensively metabolised, and more than 33 metabolites have been identified in urine. The major metabolic route is hydroxylation and oxidation at C-7 followed by further hydroxylation in the pentyl and propenyl groups. The major oxidised metabolite identified is CBD-7-oic acid containing a hydroxyethyl side chain. See INTERACTIONS WITH OTHER MEDICINES for information on drug interaction and metabolism by the cytochrome P450 enzyme system. Excretion: From the literature, elimination of oral cannabinoids from plasma is bi-phasic with an initial half-life of approximately four hours, and the terminal elimination half-lives are of the order of 24 to 36 hours or longer. Cannabinoids are distributed throughout the body; they are highly lipid soluble and accumulate in fatty tissue. The release of cannabinoids from fatty tissue is responsible for the prolonged terminal elimination half-life. Page 3 of 9 Version 1.0

4 CLINICAL TRIALS NanaBis is currently being trialled at the Royal North Shore Hospital by Prof Stephen Clarke as an adjunct for opioid analgesia for the management of intractable pain in patients diagnosed with advanced cancer. The trial is a safety, tolerability and exploratory end-point pilot study. For further information, contact Prof Luis Vitetta (luis_vitetta@medlab.co). INDICATIONS NanaBis is used to improve symptoms related to intractable pain in cancer patients. Cancer pain is mostly disease related. The chronic treatment-related pain syndromes are persistent painful complications of a cancer treatment. Patients who do not respond well to opioid analgesics, or have severe side effects from the use of traditional analgesics are in need of alternative therapeutic options. NanaBis is used as an alternative to or in combination with opioid analgesics. What is Intractable Pain? Intractable pain is defined as pain that is excruciating, constant, incurable, and of such severity that it dominates virtually every conscious moment, produces mental and physical debilitation and may produce adverse mental psychosis that can lead to self-harm for the sole purpose of stopping the pain. The common characteristics of the patient that presents with intractable pain can include the following: Pain that is constant and excruciating; Pain that reduces sleep and food intake; Pain that reduces the patient to bed-, chair-, or house-bound in the absence of opioid treatment; Pain that leads to depression, attention deficit, confusion, and self-harm tendencies; Pain where the underlying cause is incurable, non-removable, and fails to respond to customary pain therapies; Pain that elevates blood pressure and pulse rate; Pain that leads to serum adrenal hormone and immune abnormalities. CONTRAINDICATIONS NanaBis is contraindicated in patients: With hypersensitivity to cannabinoids or to any of the excipients. With any known or suspected history or family history of schizophrenia, or other psychotic illness; history of severe personality disorder or other significant psychiatric disorder other than depression associated with their underlying condition. Who are pregnant. Who are breast feeding (in view of the considerable levels of cannabinoids likely in maternal breast milk and the potential adverse developmental effects in infants. See PRECAUTIONS Use in Lactation). PRECAUTIONS Individual response to cannabis products varies widely and patients being considered for treatment with NanaBis should therefore be assessed by the prescribing doctor. Patients who then commence a trial of NanaBis should be reassessed by the prescribing doctor after four weeks of treatment. Mild or moderate dizziness is commonly reported with the use of cannabis products. This most frequently occurs in the first few weeks of treatment. Patients should take special care when consuming alcohol while using NanaBis. Using NanaBis and alcohol together may increase their effects (such as loss of balance or ability to respond quickly). Page 4 of 9 Version 1.0

5 WARNING High doses of NanaBis may increase the risk of serious psychiatric adverse events including psychosis, hallucinations, delusions, and homicidal and suicidal ideation. NanaBis is not recommended for use in children or adolescents below 18 years of age due to lack of safety and efficacy data. Psychiatric adverse events No data specific to NanaBis is currently available. As data becomes available from the ongoing clinical trial, information will be updated to reflect those findings. For further information, please contact Prof Luis Vitetta However, as THC in NanaBis is a psychoactive compound, psychological and psychiatric effects including depression, paranoia, delusional thoughts and hallucinations can be expected in a proportion of patients. Other side effects: Very common (affecting more than 1 in 10 people) - feeling dizzy or tired - feeling hungry - problems with your memory or having trouble concentrating - changed sense of taste or a dry mouth Common (affecting less than 1 in 10 people) - lack of energy or feeling weak or generally unwell - problems with your memory or having trouble concentrating - feeling abnormal or drunk - feeling sleepy or drowsy - blurred vision - constipation or diarrhoea - feeling nauseous or vomiting - loss of balance or falling over - mouth problems, including burning, pain or mouth ulcers - feeling depressed or disorientated - feeling over-excited or losing touch with reality - difficulty speaking - seeing or hearing things that are not there (hallucinations) Uncommon (affecting less than 1 in 100 people) - stomach pain - sore throat or throat irritation - mouth or teeth changing colour - irritation where NanaBis is sprayed - red and swollen mouth or peeling inside the mouth - delusional thoughts - paranoid thoughts / feeling that other people are against you - fast or irregular heartbeats, also called palpitations - fainting Reporting of adverse events: Any adverse event after administration of NanaBis, should be reported to the sponsor (Medlab Clinical Ltd) by the treating or prescribing health practitioner as soon as possible within 48 hours. In addition, it is a requirement for the treating or prescribing practitioner to report any adverse event to the Therapeutic Goods Administration (TGA) within a timeframe of 15 days. Page 5 of 9 Version 1.0

6 Genotoxicity No data specific to NanaBis is currently available. As data becomes available from the ongoing clinical trial, information will be updated to reflect those findings. For further information, please contact Prof Luis Vitetta Carcinogenicity No data specific to NanaBis is currently available. As data becomes available from the ongoing clinical trial, information will be updated to reflect those findings. For further information, please contact Prof Luis Vitetta Effects on Fertility There is insufficient experience in humans regarding the effects of NanaBis on reproduction. NanaBis should not be used during pregnancy unless the potential risks to the foetus and/or embryo are considered to be outweighed by the benefit of treatment. Paediatric Use NanaBis is not recommended for use in children or adolescents below 18 years of age due to lack of safety and efficacy data. Geriatric Use No specific studies have been carried out in elderly patients. As elderly patients may be more prone to develop some CNS adverse reactions, care should be taken in terms of personal safety such as preparation of hot food and drinks. INTERACTION WITH OTHER MEDICINES The two main components of NanaBis, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are metabolised by the cytochrome P450 enzyme system. In an in vitro study with 1:1% (v/v) THC and CBD, no relevant induction of cytochrome P450 enzymes was seen for human CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzymes in human hepatocytes, at doses of up to 1µM (314 ng/ml). When 1:1% (v/v) THC and CBD is co-administered with food, the mean Cmax and AUC for THC were 1.6- and 2.8-fold higher compared with fasting conditions. Corresponding figures for CBD were 3.3- and 5.1-fold. Concomitant treatment with the CYP3A4 inhibitor ketoconazole produced an increase in Cmax and AUC of THC (1.2- and 1.8-fold, respectively), as well as of the primary metabolite of THC (3- and 3.6- fold, respectively) and of CBD (2- and 2-fold, respectively). Therefore, if concomitant drug treatment with CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, clarithromycin) is started or stopped during treatment with 1:1% (v/v) THC and CBD, a new dose titration may be required. Following treatment with the CYP3A4 inducer rifampicin, reductions in Cmax and AUC of THC (40% and 20% reduction, respectively), its primary metabolite (85% and 87% reduction, respectively), and CBD (50% and 60% reduction, respectively), were observed. Concomitant treatment with the CYP2C19 inhibitor omeprazole resulted in no notable change in any of the pharmacokinetic parameters. Based on in vitro data, an inhibition of p-glycoprotein at the intestinal level by CBD cannot be excluded. Therefore, caution is recommended upon concomitant treatment with digoxin and other drugs being substrates for p-glycoprotein. Abuse potential Because of the psychoactive components of NanaBis, there is potential for substance abuse, and NanaBis use should be monitored for such abuse. Page 6 of 9 Version 1.0

7 DOSAGE AND ADMINISTRATION Patients being considered for treatment with NanaBis should be assessed by a doctor. Treatment must be initiated and supervised by a doctor with expertise in treating patients with chronic pain. NanaBis is for oro-buccal use only. NanaBis is intended to be used solely or in addition to the patient s current analgesia. It is recommended to take the medicine at least 15 minutes before or after meals. Adults Determining the optimal individualised dose of NanaBis may take some weeks, and side effects from either over- or under-dosing may cause temporary problems. If possible, the selected dosage should be maintained for a period of two weeks unless adverse effects such as dizziness, somnolence, fatigue or psychiatric phenomena are significant. Dosage reduction may be required in such circumstances. Titration period: A titration period is required to reach optimal dose. The number and timing of sprays will vary between patients. Start NanaBis at a dose of two sprays three times a day for two days. Increase to three sprays three times a day if pain relief is not achieved. Increase after a two-day trial of each dosage to a maximum of 24 sprays per day in three equal doses until optimal pain relief is achieved. The optimal dose is the lowest dose that achieves the highest benefit. The maximum number of consecutive sprays must not exceed 8 within a 3-hour period (max 24 sprays per day, equivalent to 30 mg THC and 30 mg CBD). Day Sprays in the morning Sprays at afternoon Sprays in the evening Total numbers of sprays per day Children NanaBis is not recommended for use in children or adolescents below 18 years of age due to lack of safety and efficacy data. Elderly No specific studies have been carried out in elderly patients. Page 7 of 9 Version 1.0

8 Patients with significant hepatic or renal impairment There are no studies in patients with impaired hepatic or renal function. However, in these subpopulations the effects of NanaBis may be exaggerated or prolonged. Frequent clinical evaluation by a clinician is recommended in these patient populations (see PRECAUTIONS). Method of administration The spray should be directed at different sites on the oro-buccal surface of the cheek changing the application site each time the product is used. If more than two sprays need to be administered, patients should wait one minute before administering the next two sprays. OVERDOSAGE There is no experience of deliberate overdose with NanaBis in patients. However, in a thorough QT study of 1:1% (v/v) THC and CBD solution in 257 subjects, with 18 sprays (100 microlitre per spray) taken over a 20-minute period twice daily, signs and symptoms of overdose/poisoning were observed. These consisted of acute intoxication type reactions including dizziness, hallucinations, delusions, paranoia, tachycardia or bradycardia with hypotension. In three of 41 subjects dosed at 18 sprays twice a day, this presented as a transient toxic psychosis which resolved upon cessation of treatment. Twenty-two subjects who received this substantial multiple of the recommended dose successfully completed the 5-day study period. In the case of overdose, treatment should be symptomatic and supportive. For information on the management of overdose, contact the Poison Information Centre on (Australia). PRESENTATION AND STORAGE CONDITIONS Presentation NanaBis is a dark-amber oro-buccal spray solution containing 8.33 mg/ml of THC and 8.33 mg/ml of CBD. The white plastic spray vial is fitted with a metering pump possessing a polypropylene dip tube and elastomer neck covered with a polyethylene cap. The metering pump delivers 150 microlitres per spray. Pack Size: 15 ml (100 sprays). Storage Conditions Store below 25 C. Store upright. Keep away from heat and direct sunlight. Once the spray vial is opened and in use, refrigerated storage is not necessary but do not store above 25 C. Special precautions for disposal Any unused product or waste material should be returned to the pharmacy which supplied the prescription. NanaBis Mediband A medical-grade silicone elastic Mediband is included in each package of NanaBis. The 1300 number on each band is provided only for use by healthcare professionals in situations of urgent medical care. It allows for 24/7 doctor-to-doctor access to allow for the best care of the patient in medical emergencies. It does not provide medical advice or services to the patient or public. NAME AND ADDRESS OF SPONSOR Medlab Clinical LTD, 66 McCauley St, Alexandria, NSW AUSTRALIA TEL: WEB: Nanabis@medlab.co NanaBis is a registered trademark of Medlab Clinical Limited, Australia NanoCelle is a registered trademark of Medlab Clinical Limited, Australia Page 8 of 9 Version 1.0

9 NanaBis is patent pending under file numbers: ; ; ; ; X; 15/ POISON SCHEDULE OF THE MEDICINE Poison schedule: Controlled Drug - Schedule 8 Page 9 of 9 Version 1.0