Presentation and Status in Health Basket
THC-rich (T10/C2): 10 g X 3 mg THC/0.6 mg CBD
THC-rich (T15/C3): 10 g X 4.5 mg THC/0.9 mg CBD
THC-rich (T20/C4): 10 g X 6 mg THC/1.2 mg CBD
Balanced (T10/C10): 10 g X 3 mg THC/3 mg CBD
CBD-rich (T5/C10): 10 g X 1.5 mg THC/3 mg CBD
CBD-rich (T3/C15): 10 g X 0.9 mg THC/4.5 mg CBD
CBD-rich (T1/C20): 10 g X 0.3 mg THC/6 mg CBD
*This product requires a license for medical cannabis
The maximum amount of cannabis allowed when starting therapy is 20 g per month. The general principle of dosing is: “Start Low, Go Slow”. This is true both for choosing a concentration and also for choosing the dose.
a) Choosing a concentration: Most patients should start on the concentration recommended below, in accordance with the indication for use. All patients should then be gradually titrated upwards to achieve the lowest dose that adequately addresses the patient’s symptoms and/or achieves the target goals of therapy, with no or tolerable adverse effects. Gradual titration will minimize adverse events.
T10/C2: CINV or pain due to chemotherapy, metastatic cancer pain, Parkinson’s pain, Tourette’s, PTSD.
T10/C10: Neuropathic pain, AIDS cachexia, multiple sclerosis spasticity, palliative care (terminal patients), PTSD.
T1/C20: Adults with recalcitrant epilepsy.
T0/C24 (This product is not available in this dosage): Pediatric patients with recalcitrant epilepsy.
Note: Concentrations of T15/C3 and T3/C15 are indicated for medical cannabis-experienced patients only.
b) Choosing a dose: Medical cannabis-naïve patients should begin therapy with 1 drop daily, to be taken preferably at night before bedtime. Thereafter, once every few days (for example every 2-5 days), as necessary, the patient can gradually increase the dose little by little, either increasing the number of intakes per day and/or the number of drops per intake. Each change should be small. As one example, a patient can start with 1 drop nightly, then 1 drop twice daily, followed by three times daily, ultimately aiming to accord with the patient’s self-reported duration of action. For example, if a patient reports efficacy for 8 hours, then the medical cannabis should be taken 3 times daily, but if the patient reports efficacy for 4 hours then the medical cannabis should be taken 6 times daily. (Note: Six times daily = 4 hours interval between intakes, is the maximum number of intakes per day.) Patients can also gradually increase the number of drops taken per intake in accordance with the patient’s self-reported efficacy. Patients should begin by increasing the number of drops (increasing by 1 drop only) at a single intake only (usually at night due to the possible sedation and dizziness), and thereafter, gradually increase the number of intakes with the new number of drops. The number of drops taken can be asymmetric and in accordance with the patient’s symptoms/daily routine. For example, if a patient reports more pain at night, the dose taken during the day can be 2 drops and the dose taken before bedtime can be 3-4 drops. If a patient reports adverse events, such as dizziness, during the titration process, then the upward increase in dosage should stopped. Depending on the nature and the severity of the adverse event, the patient should either stay on the current dose (e.g., if the event is mild and tolerable) or should reduce the next dose (e.g., if the event is moderate or non-tolerable or doesn’t abate). Once the dose is no longer associated with adverse effects, the titration process can be resumed, if appropriate/necessary, but more gradually than before. If the event is severe, dosing should be suspended until re-consideration of the risk-benefit profile and a decision regarding continued use is undertaken.
Medical cannabis experienced patients: For patients who switch from another medical cannabis product to this product, there are two options for choosing a starting dose. The first option (“washout”) is to gradually wean the patient from the previous medical cannabis product (to avoid withdrawal symptoms), followed by an adequate washout period (e.g., 1-2 weeks), and then beginning treatment with this product as for medical cannabis naïve patients (see above).
The second option (“conversion”) involves 3 steps:
a) calculating the daily intake of THC in mg with the previous medical cannabis product,
b) determining the equivalent amount of this product (i.e., number of drops) that would provide the same amount of THC per day for the chosen concentration of this product,
c) reducing this “equi-THC” dose by an appropriate amount (e.g., 30-50%) to allow for the fact that medical cannabis products are not interchangeable since bioequivalence has not been demonstrated.
If the daily intake of THC with the previous medical cannabis product is not known, preference should be given to adopting the first option (washout and then beginning therapy as for naïve patients). (Note: The conversion process is dictated by THC and not CBD since most adverse events of cannabis are due to the THC content.)
All patients: The titration process must be individualized, based on the patient’s symptoms and response to the medical cannabis. There is no fixed correlation between dose and weight, nor between dose and severity of symptoms. The 2 tables that the patient must complete regarding intake (product concentration, date, time of intake, number of drops per intake) and outcome (efficacy, adverse effects, duration of action) will guide the physician during the titration process, whether and/or how frequently to raise (or lower) the dose. The titration phase can take several weeks or more, and patients should be forewarned that the process is slow and that it may take some time to assess the efficacy and any adverse effects of the medical cannabis.
Changes after initial titration
If after 2 months the patient reports inadequate efficacy despite using the maximum number of drops (about 20 drops daily for a monthly usage of 20 g of this product), then the physician can consider one of two options (see table in full Prescribing Information):
a) Increasing the amount of this product dispensed to the patient (e.g., increase from 20 g/month to 30 g/month). An increase in usage in the monthly amount (in grams) will require a commensurate increase in the daily number of drops. Any increase in the amount dispensed is limited to 10 g/month and the increase should be done gradually over the course of 2 months.
b) Increasing the concentration of the product. An increase in the THC concentration of the product (eg, switch from T10/C10 to T15/C3) will require a commensurate reduction in the number of drops per intake in accordance with the reduction in the number of grams per month (for example, the number of drops should be reduced 30% when reducing the number of grams per month from 30 to 20). If patients then need to undergo a further titration, it should be gradual. If the change involves an increase in the CBD concentration and does not involve an increase in the THC concentration (e.g., switch from T5/C10 to T3/C15), then there is no need for a commensurate reduction in the number of drops per intake. When switching from T10/C2 to T10/C10 both options are possible.
If the patient cannot find an effective does that does not produce significant adverse effects, switching to a product with a different THC:CBD ratio may be helpful. For example, a patient who continues to complain of euphoria can be switched to a product with a lower THC content and a higher CBD content. After the switch, patients will need to undergo a further titration, which should be gradual. Physicians should take into account that it is also possible for the patient to use 2 products with different THC:CBD ratios, matching the product to their symptoms/daily routine. For example, a patient may report better outcome using a THC-dominant strain during the day and a CBD-dominant strain before bedtime.
Over time, patients may require a change in daily dose, concentration or a switch to another product with a different THC:CBD ratio, due to a progression of the disease (e.g., cancer pain), the development of tolerance, a change in concomitant medicines, or a change in a medical condition other than the cannabis-condition. Regardless of the cause, the patient should be re-titrated to effect.
During the initial titration phase and upon any change in dosage, patients should be closely monitored for efficacy and adverse effects. Once patients are stabilized on an appropriate dose, the follow up interval can be lengthened. Nevertheless, at all time during treatment with medical cannabis, patients should be periodically followed up to ensure that treatment goals continue to be met and that there are no signs of misuse/addiction.
If the patient cannot find a particular product that achieves the therapeutic target with minimal or tolerable adverse effects (even after changing the dose or changing to a different THC:CBD ratio), or if the patient shows signs of misuse or addiction, treatment with this product should be discontinued. It is recommended to gradually reduce the dose over time, performing a downward titration process that is the reverse of the upward titration process in order to prevent withdrawal symptoms.
Method of Administration: This product is administered as drops sublingually and each bottle contains about 330 drops. The patient should remove the bottle cap, rapidly turn the bottle completely upside down (i.e., not at an angle) and drop 1-9 drops of oil onto a teaspoon, in accordance with the number of drops required. The bottle should be returned rapidly to an upright position. The patient should carefully insert the teaspoon into the mouth, place it under the tongue, and remove the teaspoon slowly from the mouth, wiping the teaspoon against the underside of the tongue so that the drops remain on the underside of the tongue and the teaspoon comes out “clean”. Patients should wait at least 1 minute before swallowing the saliva to allow for submucosal absorption. After use, the patient should securely close the bottle with the bottle cap.
Most patients will require about 2-6 drops about 3-4 times per day. If a patient requires between 4-9 drops at a single intake and it is difficult for him/her to hold the full number of drops under the tongue, the patient can divide the number of drops, with a 1-2 minute interval in-between. No more than 9 drops should be taken in a single intake; if >9 drops are necessary at a single intake then it is recommended to switch to a more concentrated product in order to use fewer drops per intake.
About 5 minutes before administering the drops, patients should eat or drink something sweet to counter the reduction in blood sugar level from cannabis. Patients should wait at least 15 minutes after taking this product before eating or drinking to ensure adequate absorption. Since food could affect the bioavailability of the drops, it is preferable for the patient to take the medicine each time in the same manner with regard to meals, in order to maintain consistency.
The Israel Ministry of Health has outlined in Guidance 106 the 12 indications for which medical cannabis is indicated. According to this guidance, the 11 indications for this product are:
Chemotherapy-induced nausea and vomiting (CINV) or chemotherapy-induced pain.
Metastatic cancer pain.
Inflammatory Bowel Disease.
Spasticity of multiple sclerosis.
Pain in Parkinson’s disease.
Cachexia in AIDS.
Recalcitrant epilepsy in adults. (Note: According to Guidance 106, medical cannabis is also indicated for recalcitrant epilepsy in pediatric patients but this is not an indication for this product.)
Palliative care for terminally ill patients.
Post-traumatic stress disorder.
In general, the use of medical cannabis is indicated in patients who have adequately tried and failed conventional therapies.
Please refer to Guidance 106 for details on the specific criteria required for initiating medical cannabis and for subsequent continuation, for each of the 12 indications.
In addition, for an individual patient with a clinically significant medical condition that cannot be adequately managed by conventional therapy and which is not included as one of the 12 approved indications (eg autism, fibromyalgia), the physician can appeal to the MOH Committee for Medical Cannabis to ask for approval on an individual, exceptional basis.
See Prescribing Information for full details.
Prior, current or family history (first degree relative) of psychosis or schizophrenia or schizoaffective disorder, a history of addiction or substance abuse (including cannabis use disorder or addiction to alcohol), use in pregnancy or breastfeeding, use in patients <18 years old, bipolar disease, hypersensitivity to cannabis or coconut oil/palm kernel oil.
In patients with hepatic cancer, it is recommended not to use medical cannabis that contains THC.
Note: Some experts state that, except for hypersensitivity and breastfeeding, these are relative and not absolute contraindications. Therefore, if the decision is made to use medical cannabis in at-risk patients, such as patients with psychosis risk or substance abuse risk or bipolar disease, one should generally choose a CBD-dominant cannabis and monitor closely.
Any patient who cannot be adequately monitored following treatment initiation should not be treated with medical cannabis.
General: Use caution in patients aged 18-25 years old, patients with significant kidney or liver disease, current depression or anxiety disorder, significant cardiovascular disease (cardiac insufficiency, past or current myocardial infarction or angina pectoris, uncontrolled hypertension, cardiac arrhythmia), immunocompromised patients (relevant for CBD-rich products), patients at risk for addiction/abuse. Patients being treated for a psychiatric disorder (e.g. PTSD) should be under the care of a psychiatrist and followed up closely.
Use in hypertension and diabetes: Changes in blood pressure in hypertensive patients, and changes in blood glucose in diabetics, should be monitored after initiating therapy and following any dosage increase. Patients with hypertension or diabetes and taking anti-hypertensive medication or anti-hyperglycemic medication, respectively, may need to have their dose of medicine adjusted upon initiation of medical cannabis and following any dosage increase of medical cannabis.
Use in the elderly: Since treatment initiation and any subsequent increase in dosage may be accompanied by somnolence or dizziness, elderly or infirm patients should be cautioned regarding the risk of falling. In addition, the CNS adverse reactions could potentially have an impact on various aspects of personal safety in the elderly, such as the cooking of food and preparation of hot drinks.
Use in pediatrics: Contraindicated in pediatric patients.
Use in renal or hepatic impairment: Both THC and CBD are metabolized in the liver. The primary metabolites are 11-OH-THC and 7-OH-CBD, respectively. Approximately two-thirds undergoes enterohepatic recirculation and is eliminated in the feces and one-third is excreted in the urine. Thus, systemic exposure is dependent on both renal and hepatic function, and significant impairment of either may lead to an exaggerated or prolonged effect of medical cannabis. Such patients should be closely monitored.
See Prescribing Information for full details.
Acute reactions: Dizziness, somnolence, tiredness/fatigue, reduction in blood glucose, reduction in blood pressure, increase in pulse or tachycardia, increase in appetite (“the munchies”), redness in the eyes, headache, stomach ache, dry mouth, dry eyes, blurred vision, impaired balance and motor coordination, and cognitive effects such as impaired memory, train of thought, concentration, judgment, or psychomotor skills, disorientation, euphoria, a feeling of “heaviness” or “spaced out”, relaxation, and an altered perception of time and space or a heightened sensation. At too high dose of THC, also altered level of alertness, confusion, anxiety, panic, and at very high THC doses, cannabis can trigger psychosis/paranoia/hallucinations/ delusions, especially in at-risk patients.
Chronic reactions: Cannabis has also been linked to chronic adverse effects, including cannabis use disorder. However, the risk of these chronic effects following use of medical cannabis (rather than recreational use) is less well established.
See Prescribing Information for full details.
The field of drug interactions with medical cannabis has not been well researched, and many of the drug interactions noted below are theoretical and have not yet been demonstrated clinically. Potential drug interactions are based on either a pharmacokinetic mechanism or a pharmacodynamic mechanism.
Pharmacokinetic interactions: Both THC and CBD, the main active ingredients in medical cannabis like this product, are metabolized in the liver via CYP450 enzymes, such as 2C9 (THC), 2C19 (CBD) and 3A4 (THC and CBD).
Drugs that are strong CYP3A4 inhibitors could lead to higher THC and CBD levels, while drugs that are strong CYP3A4 inducers could lead to lower THC and CBD levels.
It is possible that strong CYP2C9 inhibitors could lead to higher THC levels. Similarly, it is possible that strong CYP2C9 inducers could lead to lower THC levels.
It is possible that strong CYP2C19 inhibitors could lead to higher CBD levels.
Similarly, it is possible that strong CYP2C19 inducers could lead to lower CBD levels.
Monitor INR if co-prescribing this product with warfarin.
CBD was shown to interact with several anti-epileptic medicines.
1. CNS depressants: Medical cannabis can have a pharmacodynamic drug interaction with other CNS depressant drugs, such as opioids, benzodiazepines, other hypnotics or sedatives, H1 receptor antagonists, and alcohol, increasing the risk or severity of somnolence, dizziness, fatigue, and ataxia or impaired balance. Discontinuation of these drugs or a reduction in their dose should be an aim of therapy with medical cannabis. Concomitant use of alcohol in particular should be discouraged to reduce risks associated with driving and risk of falls. If a patient is scheduled for surgery including the use of an anesthetic, the surgeon and anesthesiologist should be consulted.
2. Muscle relaxants: Care should also be taken when using muscle relaxants or anti-spasmodics (e.g., benzodiazepines, baclofen) since concomitant use with medical cannabis could decrease muscle tone or strength and increase the risk of falls and other accidents.
3. Anti-hyperglycemic medicines: Medical cannabis could have an additive effect on reducing serum glucose levels when given with anti-hyperglycemics. The dose of anti-hyperglycemic may need to be adjusted, particularly upon treatment initiation of medical cannabis and following any dosage increase.
4. Anti-hypertensives: Medical cannabis could have an additive effect on lowering blood pressure when given with anti-hypertensives. The dose of anti-hypertensive may need to be adjusted, particularly upon treatment initiation of medical cannabis and following any dosage increase.
5. Anti-cholinergics: Medical cannabis could have an additive effect (e.g., increase in dry mouth, drowsiness, tachycardia and dizziness), when given with anticholinergic medicines such as tricyclic antidepressants, antihistamines used for allergies.
6. Sympathomimetics: Medical cannabis could have an additive effect (e.g., tachycardia, increase in blood pressure), when given with sympathomimetics including medicines administered topically into the nose or eye, which have a potential for systemic absorption.
See Prescribing Information for full details.
Pregnancy and Lactation
Pregnancy and Breastfeeding: Medical cannabis is contraindicated during pregnancy and breastfeeding according to IMC-GCP. Both female and male patients must use an effective form of contraception not only during medical cannabis use but also for 3 months subsequent to treatment discontinuation. Some cannabis constituents can pass into the breast milk and could adversely affect the baby.
Fertility: In the literature, cannabis use has been associated with a decrease in sperm quantity and quality. The testes are rich in endocannabinoid expression.
There are no recorded deaths due solely to cannabis in the literature, but the possibility of overdose in pediatric patients cannot be definitively excluded. Cannabis is not thought to be associated with respiratory depression like opioids since there are no CB1 receptors in the medulla oblongata (the brain respiratory center). Expected symptoms of overdose are those reflective for an excessive dose (hypotension, tachycardia, hypoglycemia, anxiety, panic or psychotic reactions). In the case of overdose, treatment should be symptomatic and supportive.
*This product requires a license for medical cannabis
Effects on ability to drive and use machines: Medical cannabis can lead to somnolence, dizziness and several other adverse effects (such as a decrease in judgment and concentration, impaired performance of motor skills and a slowing of the reaction time), which can impair driving ability and the ability to operate heavy/dangerous machinery. This could result in an increase in the risk of accidents. Usually these adverse effects are more prominent at the beginning of therapy and following any increase in dosage.
Transportation Ordinance Section 64b and Transportation Regulations in Israel determine under which conditions it is permissible or forbidden to drive while under therapy with medical cannabis, and one should always act in accordance with these ordinance/regulations. Patients should be informed that driving not in accordance with the Transportation Ordinance /Regulations and while any level of cannabis or its metabolites may be detected in the blood or urine is a violation of Traffic Ordinance 64b, regardless of driving ability.
Note: Metabolites of cannabis may be found in the urine following last use for up to 21-30 days in long-term users. This is because cannabinoids are highly lipophilic and they accumulate in the fatty tissue. Slow release from the fatty tissue leads to a prolonged terminal elimination half-life of ~24-36 hours for THC and ~18-32 hours for CBD.
Food: About 5 minutes before administering the drops, patients should eat or drink something sweet to counter the reduction in blood sugar level from cannabis. Patients should wait at least 15 minutes after taking this product before eating or drinking to ensure adequate absorption. Since food could affect the bioavailability of the drops, it is preferable for the patient to take the medicine each time in the same manner with regard to meals, in order to maintain consistency.