Zipan

Contraindications

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What is the most important information I should know about Zipan?

You should not take Zipan if you are allergic to it, if you have ever been addicted to drugs or alcohol, or if you have ever attempted suicide. Do not take Zipan while you are intoxicated (drunk) or taking any of the following: alcohol or street drugs, narcotic pain medicine, sedatives or tranquilizers, or medicine for depression, anxiety, or mental illness.

Seizures (convulsions) have occurred in some people taking Zipan. Zipan may be more likely to cause a seizure if you have a history of seizures or head injury, a metabolic disorder, or if you are taking certain medicines such as antidepressants, muscle relaxers, narcotic, or medicine for nausea and vomiting.

Seek emergency medical attention if you think you have used too much of this medicine. A Zipan overdose can be fatal.

Zipan may be habit-forming and should be used only by the person it was prescribed for. Keep the medication in a secure place where others cannot get to it.

Do not crush the Zipan tablet. This medicine is for oral (by mouth) use only. Powder from a crushed tablet should not be inhaled or diluted with liquid and injected into the body. Using this medicine by inhalation or injection can cause life-threatening side effects, overdose, or death.

Undesirable effects

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What are the possible side effects of Zipan?

The most commonly reported adverse reactions are dizziness, nausea, constipation, headache, somnolence and vomiting as presented in Table 1.1.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Zipan® was administered to 550 patients during the double-blind or open-label extension periods in studies of chronic non-malignant pain. Of these patients, 375 were 65 years old or older. Table 1.1 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. The overall incidence rates of adverse experiences in these trials were similar for Zipan® and the active control groups, acetaminophen with codeine, and aspirin with codeine; however, the rates of withdrawals due to adverse events appeared to be higher in the Zipan® group. In the Zipan treatment groups, 16.8-24.5% of patients withdrew due to an AE, compared to 9.6-11.6% for acetaminophen with codeine and 18.5% for aspirin with codeine.

Table 1.1: Cumulative Incidence of Adverse Reactions for Zipan® in Chronic Trials of Non-Malignant Pain

Incidence 1% to less than 5% possibly causally related: the following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with Zipan® exists.

Body as a Whole: Malaise.

Cardiovascular: Vasodilation.

Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder.

Gastrointestinal: Abdominal pain, Anorexia, Flatulence.

Musculoskeletal: Hypertonia.

Skin: Rash.

Special Senses: Visual disturbance.

Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention.

Incidence less than 1%, possibly causally related: the following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials and/or reported in post-marketing experience.

Body as a Whole: Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma).

Cardiovascular: Orthostatic hypotension, Syncope, Tachycardia.

Central Nervous System: Abnormal gait, Amnesia, Cognitive dysfunction, Depression, Difficulty in concentration, Hallucinations, Paresthesia, Seizure, Tremor.

Respiratory: Dyspnea.

Skin: Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles.

Special Senses: Dysgeusia.

Urogenital: Dysuria, Menstrual disorder.

Other adverse experiences, causal relationship unknown

A variety of other adverse events were reported infrequently in patients taking Zipan® during clinical trials and/or reported in post-marketing experience. A causal relationship between Zipan® and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.

Cardiovascular: Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism.

Central Nervous System: Migraine, Speech disorders.

Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.

Laboratory Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria.

Sensory: Cataracts, Deafness, Tinnitus.

Adverse events which have been reported with the use of Zipan products include: allergic reactions (including anaphylaxis, angioneurotic edema and urticaria), bradycardia, convulsions, drug dependence, drug withdrawal (including agitation, anxiety, gastrointestinal symptoms, hyperkinesia, insomnia, nervousness, tremors), hyperactivity, hypoactivity, hypotension, worsening of asthma and respiratory depression. Other adverse events which have been reported with the use of Zipan products and for which a causal association has not been determined include: difficulty concentrating, hepatitis, liver failure, pulmonary edema, Stevens-Johnson syndrome and suicidal tendency.

Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma) has been reported with Zipan when used concomitantly with other serotonergic agents such as SSRIs and MAOIs. Post-marketing experience with the use of Zipan-containing products included rare reports of delirium, miosis, mydriasis, and speech disorder, and very rare reports of movement disorder including dyskinesia and dystonia.

Cases of hypoglycemia have been reported in patients taking Zipan, mostly in patients with pre-disposing risk factors, including diabetes, elderly and renal insufficiency. Caution should be exercised when prescribing Zipan to diabetic patients. More frequent monitoring of blood glucose levels may be appropriate, including at initiation or dose increase.

Zipan may induce psychic and physical dependence of the morphine-type (μ-opioid). Dependence and abuse, including drug-seeking behaviour and taking illicit actions to obtain the drug are not limited to those patients with a prior history of opioid dependence. The risk in patients with substance abuse has been observed to be higher. Zipan is associated with craving and tolerance development.

A Risk Management program to support the safe and effective use of Zipan® has been established. The following are considered to be the essential components of the Risk Management program:

1. Commitment to not emphasize or highlight the scheduling status of Zipan® (i.e., not listed under a schedule to the CDSA) in its advertising or promotional activities.
2. Inclusion of a PAAB-approved fair balance statement in all Zipan® advertising and promotional materials.
3. Assurance that health-care education activities on pain management with Zipan® include balanced, evidence-based and current information. Commitment to take reasonable actions to inform health-care professionals that there is Health Canada-approved patient information on benefits and risks, and to ensure that this information can be readily accessed through electronic and/or hard copy sources.

Withdrawal symptoms may occur if Zipan® is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Other symptoms that have been seen less frequently with Zipan® discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support.

Therapeutic indications

Zipan® (Zipan hydrochloride) is indicated for the management of moderate to moderately severe pain in adults.

Healthy elderly subjects aged 65 to 75 years administered Zipan have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. Zipan® should be administered with greater caution in patients older than 75 years, due to the greater potential for adverse events in this population.

The safety and effectiveness of Zipan® have not been studied in the pediatric population. Therefore, use of Zipan® tablets is not recommended in patients under 18 years of age.

Zipan is a narcotic-like pain reliever.

Zipan is used to treat moderate to severe pain.

The extended-release form of Zipan is for around-the-clock treatment of pain. This form of Zipan is not for use on an as-needed basis for pain.

Zipan may also be used for purposes not listed in this medication guide.

Name of the medicinal product

Qualitative and quantitative composition

A synthetic opioid that is used as the hydrochloride. It is an opioid analgesic that is primarily a mu-opioid agonist. It has actions and uses similar to those of morphine. It also has a depressant action on the cough center and may be given to control intractable cough associated with terminal lung cancer. Zipan is also used as part of the treatment of dependence on opioid drugs, although prolonged use of methadone itself may result in dependence. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1082-3)

Special warnings and precautions for use

Use Zipan orally disintegrating tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Zipan orally disintegrating tablets by mouth with or without food.
• To open the blister pack, peel back the foil on the blister. Do NOT push the tablet through the foil.
• Do NOT chew, break, or split the tablet.
• To take Zipan orally disintegrating tablets, place the tablet in your mouth. Let it dissolve, and then swallow it with saliva. Zipan orally disintegrating tablets may be taken with or without water.
• If you miss a dose of Zipan orally disintegrating tablets and you are taking it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Zipan orally disintegrating tablets.

Pain management:

Extended release: Management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Immediate release: Management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of use: Reserve Zipan for use in patients for whom alternative treatment options (eg, nonopioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Zipan ER is not indicated as an as-needed analgesic.

Data from mostly placebo-controlled clinical trials suggest that Zipan may be beneficial for the treatment of premature ejaculation.

Dosage (Posology) and method of administration

Zipan® is an extended-release formulation intended for once a day dosing in adults aged 18 years and older. The capsules must be swallowed whole with liquid and must not be split, chewed, dissolved or crushed. Chewing, crushing or splitting the capsule could result in the uncontrolled delivery of Zipan, in overdose and death.

Do not administer Zipan® at a dose exceeding 300 mg per day. Do not use Zipan® more than once daily or concomitantly with other Zipan products.

Initiate treatment with Zipan® at a dose of 100 mg once daily and titrated up as necessary by 100 mg increments every five days to achieve a balance between relief of pain and tolerability.

Calculate the 24-hour Zipan IR dose and initiate a total daily dose of Zipan® rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with Zipan®, some patients maintained on Zipan IR products may not be able to convert to Zipan®.

Initiate dosing of an elderly patient (over 65 years of age) should be initiated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. Zipan® should be administered with even greater caution in patients over 75 years, due to the greater frequency of adverse events seen in this population.

The limited availability of dose strengths and once daily dosing of Zipan® do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Do not use Zipan® in patients with creatinine clearance less than 30 mL/min.

The limited availability of dose strengths and once daily dosing of Zipan hydrochloride extended-release capsules do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Do not use Zipan® in patients with severe hepatic impairment (Child-Pugh Class C).

Withdrawal symptoms may occur if Zipan® is discontinued abruptly. Clinical experience with Zipan suggests that withdrawal symptoms may be reduced by tapering Zipan®.

Zipan® may be taken without regard to food.

Interaction with other medicinal products and other forms of interaction

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What other drugs will affect Zipan?

CYP2D6 and CYP3A4 Inhibitors: Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors, such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of Zipan increasing the risk for serious adverse events including seizures and serotonin syndrome.

There have been postmarketing reports of serotonin syndrome with use of Zipan and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when Zipan is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John's Wort. If concomitant treatment of Zipan with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Based on the mechanism of action of Zipan and the potential for serotonin syndrome, caution is advised when Zipan is coadministered with a triptan. If concomitant treatment of Zipan with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of Zipan. Because carbamazepine increases Zipan metabolism and because of the seizure risk associated with Zipan, concomitant administration of Zipan and carbamazepine is not recommended.

Coadministration of quinidine with Zipan resulted in a 50-60% increase in Zipan exposure and a 50-60% decrease in M1 exposure. The clinical consequences of these findings are unknown.

Post-marketing surveillance of Zipan has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.

In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of Zipan.

Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John's Wort, with Zipan may affect the metabolism of Zipan leading to altered Zipan exposure.

In vitro drug interaction studies in human liver microsomes indicate that Zipan has no effect on quinidine metabolism. In vitro studies indicate that Zipan is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when administered concomitantly at therapeutic doses. Zipan is a mild inducer of selected drug metabolism pathways measured in animals.