Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2022 Publisher: AFT Pharmaceuticals Limited, PO Box 33-203, Takapuna, Auckland 0740, Phone: 0800 423 823
Treatment with Rubifen is not indicated in all cases of Attention-Deficit/Hyperactivity disorder, and should be considered only after detailed history-taking and evaluation. The decision to prescribe Rubifen should depend on an assessment of the severity of symptoms and their appropriateness to the child’s age, and not simply on the presence of one or more abnormal behavioural characteristics. Where these symptoms are associated with acute stress reactions, treatment with Rubifen is usually not indicated.
Sudden death has been reported in association with the use of stimulants of the central nervous system Page 5 of 17 at usual doses in patients with structural cardiac abnormalities or other serious problems. A causal relationship with stimulant products has not been established since some of these conditions alone may carry an increased risk of sudden death. Stimulant products generally should not be used in patients with known structural cardiac abnormalities or other serious cardiac disorders that may increase the risk of sudden death due to sympathomimetic effects of a stimulant drug. Before initiating Rubifen treatment, patients should be assessed for pre-existing cardiovascular disorders and a family history of sudden death and ventricular arrhythmia (see Section 4.2).
Rubifen is contraindicated in patients with severe hypertension (see Section 4.3). Methylphenidate increases heart rate and systolic and diastolic blood pressure. Therefore, caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension. Severe cardiovascular disorders are contraindicated (see Section 4.3).
Blood pressure should be monitored at appropriate intervals in all patients taking Rubifen, especially those with hypertension. Patients who develop symptoms suggestive of cardiac disease during Rubifen treatment should undergo a prompt cardiac evaluation.
Misuse of stimulants of the central nervous system, including Rubifen, may be associated with sudden death and other serious cardiovascular adverse events.
Patients with pre-existing central nervous system (CNS) abnormalities, e.g., cerebral aneurysm and/or other vascular abnormalities such as vasculitis or pre-existing stroke should not be treated with Rubifen. Patients with additional risk factors (history of cardiovascular disease, concomitant medications that elevate blood pressure) should be assessed regularly for neurological/psychiatric signs and symptoms after initiating treatment with Rubifen (see above, paragraph on Cardiovascular Conditions and Section 4.5).
Aggressive behaviour, marked anxiety, or agitation are often observed in patients with ADHD, and have been reported in patients treated with methylphenidate tablets (see section 4.8 Undesirable effects). Anxiety led to discontinuation of methylphenidate tablets in some patients. It is recommended to monitor patients beginning treatment with methylphenidate tablets for the appearance of, or worsening of, aggressive behaviour, marked anxiety, or agitation.
Co-morbidity of psychiatric disorders in ADHD is common and should be taken into account when prescribing stimulant products. Prior to initiating treatment with Rubifen, patients should be assessed for pre-existing psychiatric disorders and a family history of psychiatric disorders (see Section 4.2).
Treatment of ADHD with stimulant products including Rubifen should not be initiated in patients with acute psychosis, acute mania or acute suicidality. These acute conditions should be treated and controlled before ADHD treatment is considered.
In the case of emergent psychiatric symptoms or exacerbation of pre-existing psychiatric symptoms, Rubifen should not be given to patients unless the benefit outweighs the potential risk.
Psychotic symptoms, including visual and tactile hallucinations or mania have been reported in patients administered usual prescribed doses of stimulant products, including Rubifen (see Section 4.8). Physicians should consider treatment discontinuation.
Emergent aggressive behaviour or an exacerbation of baseline aggressive behaviour has been reported during stimulant therapy, including Rubifen. However, patients with ADHD may experience aggression as part of their medical condition. Therefore causal association with treatment is difficult to assess. Physicians should evaluate the need for adjustment of treatment regimen in patients experiencing these behavioural changes, bearing in mind that upwards or downwards titration may be appropriate. Treatment interruption can be considered.
Patients with emergent suicidal ideation and behaviour during treatment for ADHD should be evaluated immediately by their physician. The physician should initiate appropriate treatment of the underlying psychiatric condition and consider a possible change in the ADHD treatment regimen.
Methylphenidate is associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported. It is recommended that the family history be assessed, and that the patient is clinically evaluated for tics or Tourette’s syndrome before initiating methylphenidate. Regular monitoring for the emergence or worsening of tics or Tourette’s syndrome during treatment with methylphenidate is recommended at every dose adjustment and every visit, and treatment discontinued if clinically appropriate.
Serotonin syndrome has been reported following co-administration of methylphenidate with serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs) and serotonin- norepinephrine reuptake inhibitors (SNRIs). The concomitant use of methylphenidate and serotonergic drugs is not recommended as this may lead to the development of serotonin syndrome. The symptoms of serotonin syndrome may include mental status changes (e.g. agitation, hallucinations, delirium, and coma), autonomic instability (e.g. tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g. tremor, rigidity, myoclonus, hyperreflexia, and incoordination), seizures, and/or gastrointestinal symptoms (e.g. nausea, vomiting, and diarrhoea). Prompt recognition of these symptoms is important so that treatment with methylphenidate and serotonergic drugs can be immediately discontinued and appropriate treatment instituted (see Section 4.5).
Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both paediatric and adult patients. Priapism generally developed after some time on the drug, often subsequent to an increase in dose. Priapism has also been reported during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.
Moderately reduced weight gain and slight growth retardation have been reported with the long-term use of stimulants, including Rubifen, in children (see Section 4.8).
Growth should be monitored as clinically necessary during treatment with Rubifen, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
Rubifen should be used with caution in patients with epilepsy as clinical experience has shown that it can cause an increase in seizure frequency in a small number of such patients. If seizure frequency increases, Rubifen should be discontinued.
Chronic abuse of Rubifen can lead to marked tolerance and psychological dependence with varying degrees of abnormal behaviour. Frank psychotic episodes may occur, especially with parenteral abuse. Clinical data indicate that children given Rubifen are not more likely to abuse drugs as adolescents or adults.
Caution is called for in emotionally unstable patients, such as those with a history of drug dependence or alcoholism, because they may increase the dosage on their own initiative.
Careful supervision is required during drug withdrawal, since this may unmask depression as well as the effects of chronic over activity. Some patients may require long-term follow-up.
The long-term safety and efficacy profiles of Rubifen are not fully known. Patients requiring longterm therapy should therefore be carefully monitored and complete and differential blood counts and a platelet count performed periodically. In the event of haematological disorders appropriate medical intervention should be considered (see Section 4.8).
Methylphenidate should not be used in children under 6 years of age, since safety and efficacy in this age group have not been established.
In a conventional study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10). When the animals were tested as adults (postnatal weeks 13- 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose of 100 mg/kg/day (about 58-fold higher than the MRHD on a mg/kg basis).
With methylphenidate, sister chromatid exchange and chromosome aberrations were elevated in one in vitro study in Chinese Hamster Ovary (CHO) cells. However, no genotoxicity effects were seen in several other assays, including no mutagenic effects in three in vitro tests (Ames reverse mutation test, mouse lymphoma forward mutation test, human lymphocyte chromosome aberration test) and no evidence of clastogenic or aneugenic effects in two in vivo mouse bone marrow (micronucleus tests, at doses up to 250 mg/kg. B6C3F1 mice from the same strain that showed liver tumours in the cancer bioassay were used in one of these studies. Additionally, there was no genotoxic potential as assessed by measuring cII mutations in the liver and micronuclei in peripheral reticulocytes in the Big Blue mouse, micronuclei in peripheral blood reticulocytes, HPRT mutations and chromosomal aberrations in peripheral blood lymphocytes of rhesus monkeys. Pig A locus mutations in adolescent rats, micronucleated reticulocyte frequencies in blood and DNA damage in blood, brain, and liver cells of adult male rats treated for 28 consecutive days, and by measuring micronuclei in mouse peripheral blood erythrocytes.
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas (a benign tumour) and, in males only, an increase in hepatoblastomas (a malignant tumour) at daily doses of approximately 60 mg/kg/day (about 35- fold-higher than the MRHD on a mg/kg basis). Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no overall increase in the number of malignant hepatic tumours. The mouse strain used is particularly sensitive to the development of hepatic tumours. It is thought that hepatoblastomas might be due to nongenotoxic mechanisms such as an increase in hepatic cell proliferation. This is consistent with the increase in liver weights observed in this mouse carcinogenicity study.
Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day (about 26-fold higher than the MRHD on a mg/kg basis).
Rubifen may decrease the effectiveness of drugs used to treat hypertension.
Rubifen should be used with caution in patients being treated with drugs that elevate blood pressure (see also paragraph on Cerebrovascular Conditions in Section 4.4).
Because of possible hypertensive crisis, Rubifen is contraindicated in patients being treated (currently or within the preceding 2 weeks) with MAO-inhibitors (see Section 4.3).
Alcohol may exacerbate the adverse CNS effects of psychoactive drugs, including Rubifen. It is therefore advisable for patients to abstain from alcohol during treatment.
There is a risk of sudden blood pressure and heart rate increase during surgery. If surgery is planned, Rubifen should not be taken on the day of surgery.
Serious adverse events including sudden death, have been reported in concomitant use with clonidine, although no causality for the combination has been established.
As an inhibitor of dopamine reuptake, methylphenidate may be associated with pharmacodynamic interactions when co-administered with direct and indirect dopamine agonists (including DOPA and tricyclic antidepressants) as well as dopamine antagonists (antipsychotics, e.g. haloperidol). The coadministration of Rubifen with antipsychotics is not recommended because of the counteracting mechanism of action.
The concomitant use of methylphenidate and serotonergic drugs is not recommended as this may lead to the development of serotonin syndrome (see Section 4.4).
Methylphenidate has been shown to increase extracellular serotonin and norepinephrine and appears to have weak potency in binding serotonin transporter.
Methylphenidate is not metabolized by cytochrome P450 to a clinically relevant extent. Inducers or inhibitors of cytochrome P450 are not expected to have any relevant impact on Rubifen pharmacokinetics. Conversely, the d- and l-enantiomers of methylphenidate in Rubifen did not relevantly inhibit cytochrome P450 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A. Rubifen co-administration did not increase plasma concentrations of the CYP2D6 substrate desipramine.
Case reports suggested a potential interaction of methylphenidate with coumarin anticoagulants, some anticonvulsants (e.g. phenobarbital, phenytoin, primidone), phenylbutazone, and tricyclic antidepressants but pharmacokinetic interactions were not confirmed when explored at larger sample sizes. The dosage of these drugs might have to be reduced.
An interaction with the anticoagulant ethyl biscoumacetate in 4 subjects was not confirmed in a subsequent study with a larger sample size (n=12).
Other specific drug-drug interaction studies with m have not been performed in vivo.
Methylphenidate may induce false positive laboratory tests for amphetamines, particularly with immunoassays screen test.
Methylphenidate is potentially teratogenic in rabbits (see non-clinical safety data).
The safety of methylphenidate for use during human pregnancy has not been established. Data from a cohort study of in total approximately 3,400 pregnancies exposed in the first trimester do not suggest an increased risk of overall birth defects. There was a small increased occurrence of cardiac malformations (pooled adjusted relative risk, 1.3; 95 % CI, 1.0-1.6) corresponding to 3 additional infants born with congenital cardiac malformations for every 1000 women who receive methylphenidate during the first trimester of pregnancy, compared with non-exposed pregnancies.
Medicines should only be prescribed in pregnancy when the expected benefits to the mother outweigh any potential risks to the mother and foetus. If possible, medicines should be used at the lowest effective dose for the shortest possible duration. Careful consideration and discussion of the risks and benefits of the medicines should be taken in the management of pregnant women or women intending to become pregnant. Women of child-bearing potential should be fully informed of the risks and benefits of the use of methylphenidate during pregnancy.
Methylphenidate is considered to be possibly teratogenic in rabbits. Spina bifida with malrotated hindlimbs was observed in two separate litters at a dose of 200 mg/kg/day. Exposure (AUC) at this dose was approximately 5.1 times higher than the extrapolated exposure at the maximum recommended human dose (MRHD). Exposure at the next lower dose, wherein no spina bifida was found, was 0.7 times the extrapolated exposure at MRHD. A second study was conducted with a high dose of 300 mg/kg, which was considered maternally toxic. No spina bifida was seen, however, in 12 litters (92 foetuses) surviving. Exposure (AUC) at 300 mg/kg was 7.5 times the extrapolated exposure at MRHD.
Methylphenidate is not teratogenic in rats. Development foetal toxicity was noted at a high dose of 75 mg/kg (20.9 times higher than the AUC at MRHD) and consisted of an increase of the instance of foetuses with delayed ossification of the skull and hyoid bones as well as foetuses with short supernumerary ribs.
When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day (about 26-fold higher than the MRHD on a mg/kg basis), offspring body weight gain was decreased at the highest dose, but no other effects on postnatal development were observed.
Case reports showed that methylphenidate was distributed into breast milk reaching a milk-to-plasma ration of approximately 2.5 (see Section 5.2).
A decision should be made whether to abstain from breast-feeding or to abstain from methylphenidate therapy, taking into account the benefit of breast-feeding to the child and the benefit of therapy to the mother.
It is not known whether the active substance of Rubifen and/or its metabolites pass into breast milk, but for safety reasons, breast-feeding mothers should not use Rubifen.
When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day (about 26-fold higher than the MRHD on a mg/kg basis), offspring body weight gain was decreased at the highest dose, but no other effects on postnatal development were observed.
No human data on the effect of methylphenidate on fertility are available. Methylphenidate did not impair fertility in male or female mice.
Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted over two generations of mice continuously receiving methylphenidate doses of up to 160 mg/kg/day (about 90-fold higher than the MRHD on a mg/kg basis).
Rubifen may cause dizziness, drowsiness, blurred vision, hallucinations or other CNS side effects (see Section 4.8).
Patients experiencing such side effects should refrain from driving, operating machinery, or engaging in other potentially hazardous activities.
Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of methylphenidate based on the comprehensive assessment of the available adverse event information. A causal relationship with methylphenidate cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse Drug Reactions (ADRs) in either the paediatric or adult double-blind studies may be relevant for both patient populations.
The safety of methylphenidate tablets was evaluated in 639 paediatric patients (children and adolescents) with ADHD who participated in 4 placebo-controlled, double-blind clinical trials. The information presented in this section was derived from pooled data.
Adverse Drug Reactions (ADRs) reported by ≥1% of methylphenidate tablets-treated children and adolescent subjects and more frequently than placebo in these trials are shown in below table.
Adverse Drug Reactions Reported by ≥1% of methylphenidate tablets-Treated Children and Adolescent Subjects and More Frequently than Placebo in 4 Placebo-Controlled, Double-Blind Clinical Trials:
| System/Organ Class Adverse Drug Reaction | Methylphenidate tablets (n = 321) % | Placebo (n = 318) % |
|---|---|---|
| Infections and Infestations | ||
| Nasopharyngitis | 2.8 | 2.2 |
| Psychiatric Disorders | ||
| Insomnia | 2.8 | 0.3 |
| Nervous System Disorders | ||
| Headache | 10.6 | 11.9 |
| Dizziness | 1.9 | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||
| Cough | 1.9 | 0.9 |
| Oropharyngeal Pain | 1.2 | 0.9 |
| Gastrointestinal Disorders | ||
| Abdominal Pain upper | 6.2 | 3.8 |
| Vomiting | 2.8 | 1.6 |
| General Disorders and Administration Site Conditions | ||
| Pyrexia | 2.2 | 0.9 |
* Terms of Initial insomnia (methylphenidate tablets = 0.6%) and Insomnia (methylphenidate tablets = 2.2%) are combined into Insomnia
The majority of ADRs were mild to moderate in severity.
The safety of methylphenidate tablets was evaluated in 905 adult subjects with ADHD who participated in 3 placebo-controlled, double-blind clinical trials. The information presented in this section was derived from pooled data.
Adverse Drug Reactions (ADRs) reported by ≥1% of methylphenidate tablets-treated adult subjects in these trials are shown in below table.
Adverse Drug Reactions Reported by ≥1% of methylphenidate tablets-Treated Adult Subjects in 3 PlaceboControlled, Double-Blind Clinical Trials:
| System/Organ Class Adverse Drug Reaction | Methylphenidate tablets (n = 596) % | Placebo (n = 309) % |
|---|---|---|
| Infections and Infestations | ||
| Upper respiratory tract infection | 1.7 | 1.0 |
| Sinusitis | 1.3 | 1.0 |
| Metabolism and Nutrition Disorders | ||
| Decreased appetite | 24.8 | 6.1 |
| Anorexia | 4.2 | 1.3 |
| Psychiatric disorders | ||
| Insomnia | 13.3 | 7.8 |
| Anxiety | 8.4 | 2.9 |
| Initial insomnia | 5.7 | 2.6 |
| Depressed mood | 4.4 | 2.6 |
| Restlessness | 4.0 | 0 |
| Agitation | 3.2 | 0.6 |
| Nervousness | 2.3 | 0.6 |
| Bruxism | 1.5 | 0.6 |
| Depression | 1.5 | 0.6 |
| Affect lability | 1.3 | 0.6 |
| Libido decreased* | 1.5 | 0.6 |
| Panic attack | 1.5 | 0.3 |
| Tension | 1.5 | 0.3 |
| Aggression | 1.2 | 0.6 |
| Confusional state | 1.0 | 0.3 |
| Nervous system disorders | ||
| Headache | 24.2 | 18.8 |
| Dizziness | 7.4 | 5.5 |
| Tremor | 3.4 | 0.6 |
| Paraesthesia | 1.2 | 0 |
| Tension headache | 1.0 | 0.3 |
| Eye disorders | ||
| Accommodation disorder | 1.3 | 0 |
| Vision blurred | 1.3 | 1.0 |
| Ear and labyrinth disorders | ||
| Vertigo | 2.0 | 0.3 |
| Cardiac disorders | ||
| Tachycardia | 6.0 | 0 |
| Palpitations | 4.5 | 0.6 |
| Vascular Disorders | ||
| Hypertension | 2.2 | 1.6 |
| Hot flush | 1.3 | 0.6 |
| Respiratory, Thoracic and Mediastinal Disorders | ||
| Oropharyngeal pain | 1.5 | 1.3 |
| Cough | 1.2 | 1.0 |
| Dyspnoea | 1.2 | 0.6 |
| Gastrointestinal disorders | ||
| Dry mouth | 15.1 | 3.6 |
| Nausea | 14.3 | 4.9 |
| Dyspepsia | 2.0 | 1.9 |
| Vomiting | 1.8 | 0.6 |
| Constipation | 1.5 | 0.6 |
| Skin and Subcutaneous Tissue Disorders | ||
| Hyperhidrosis | 5.7 | 1.3 |
| Musculoskeletal and Connective Tissue Disorders | ||
| Muscle tightness | 1.3 | 0 |
| Muscle spasm | 1.0 | 0.3 |
| Reproductive System and Breast Disorders | ||
| Erectile dysfunction | 1.0 | 0.3 |
| General Disorders and Administration Site Conditions | ||
| Irritability | 5.2 | 2.9 |
| Fatigue | 4.7 | 4.2 |
| Thirst | 1.8 | 0.6 |
| Asthenia | 1.2 | 0 |
| Investigations | ||
| Weight decreased | 8.7 | 3.6 |
| Heart rate increased | 3.0 | 1.9 |
| Blood pressure increased | 2.5 | 1.9 |
| Alanine aminotransferase increased | 1.0 | 0 |
* The adverse reaction libido decreased includes the preferred term loss of libido
The majority of ADRs were mild to moderate in severity.
The safety of methylphenidate tablets was evaluated in 3782 paediatric and adult subjects with ADHD who participated in 12 open-label clinical trials. The information presented in this section was derived from pooled data.
Adverse Drug Reactions (ADRs) reported by ≥1% of methylphenidate tablets -treated subjects in these trials and not listed in above tables are shown in the below table.
Adverse Drug Reactions Reported by ≥1% of methylphenidate tablets-Treated Subjects in 12 Open-Label Clinical Trials:
| System/Organ Class Adverse Drug Reaction | Methylphenidate tablets (n = 3782) % |
|---|---|
| Psychiatric Disorders | |
| Tic | 2.0 |
| Mood swings | 1.1 |
| Nervous System Disorders | |
| Somnolence | 1.0 |
| Gastrointestinal disorders | |
| Diarrhea | 2.4 |
| Abdominal discomfort | 1.3 |
| Abdominal pain | 1.2 |
| Skin and Subcutaneous Tissue Disorders | |
| Rash | 1.3 |
| General Disorders and Administration Site Conditions | |
| Feeling jittery | 1.4 |
The majority of ADRs were mild to moderate in severity.
Additional ADRs that occurred in <1% of methylphenidate tablets-treated paediatric and adult subjects in the double-blind and open-label clinical datasets are listed in the below table.
Adverse Drug Reactions Reported by <1% of methylphenidate tablets-Treated Pediatric and Adult Subjects in Either Double-Blind or Open-Label Clinical Trials:
Blood and Lymphatic System Disorders: Leukopenia
Psychiatric Disorders: Anger, Sleep disorder, Hypervigilance, Tearfulness, Mood altered
Nervous System Disorders: Psychomotor hyperactivity, Sedation, Lethargy
Eye Disorders: Dry eye
Skin and Subcutaneous Tissue Disorders: Rash macular
Investigations: Cardiac murmur
ADRs identified during postmarketing experience with methylphenidate tablets are included in the below table. The frequencies are provided according to the following convention: Very common ≥1/10, Common ≥1/100 and <1/10, Uncommon ≥1/1000 and <1/100, Rare ≥1/10000 and <1/1000, Very rare <1/10000, including isolated reports.
Adverse Drug Reactions Identified During Postmarketing Experience with methylphenidate tablets by Frequency Category Estimated from Spontaneous Reporting Rates:
Very rare: Pancytopenia, Thrombocytopenia, Thrombocytopenic, Purpura
Rare: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions and Exanthemas NEC
Very rare: Disorientation, Hallucination, Hallucination Auditory, Hallucination Visual, Mania, Logorrhoea, libido disorder*
Very rare: Convulsion, Grand Mal Convulsion, Dyskinesia, Cerebrovascular disorder (including cerebral vasculitis, cerebral haemorrhage, cerebral arteritis, cerebral vascular occlusion)
Very rare: Diplopia, Mydriasis, Visual Impairment
Very rare: Angina Pectoris, Bradycardia, Extrasystoles, Supraventricular Tachycardia, Ventricular Extrasystoles
Very rare: Raynaud’s Phenomenon
Very rare: Alopecia, Erythema
Very rare: Hepatocellular injury, Acute hepatic failure
Very rare: Arthralgia, Myalgia, Muscle Twitching
Very rare: Priapism
Rare: Therapeutic Response Decreased
Very rare: Chest Pain, Chest Discomfort, Drug Effect Decreased, Hyperpyrexia
Very rare: Blood Alkaline Phosphatase Increased, Blood Bilirubin Increased, Hepatic Enzyme Increased, Platelet Count Decreased, White Blood Cell Count Abnormal
NEC = not elsewhere classified
* The adverse reaction libido disorder includes terms apart from those associated with decreases in libido
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/
None known.
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