Dynafil 100 Mg Film-Coated Tablets

DYNAFIL is indicated only for the treatment of erectile dysfunction. DYNAFIL IS NOT AN APHRODISIAC.

Posology

Adults

The recommended oral dose is 50 mg, taken if needed once a day approximately one hour before sexual intercourse. The dose may be increased depending on the efficacy and toleration to 100 mg, or decreased to 25 mg using another formulation. Neither DYNAFIL 50 mg nor DYNAFIL 100 mg have score lines to permit halving, a 25 mg dose cannot be achieved by splitting these tablets. Another formulation should be used to achieve the 25 mg dose. The maximum recommended dosing frequency is once per day.

Several factors can lead to increased plasma levels of DYNAFIL

• Age over 65: This can result in a 40% increase in the area under the curve (AUC).
• Liver impairment: Conditions such as cirrhosis can cause an 80% increase.
• Severe kidney impairment: Specifically, a creatinine clearance of 30 mL/min or less can lead to a 100% increase.

Special populations

Elderly and patients with impaired renal or hepatic function

In patients with reduced clearance, increased DYNAFIL plasma levels and an increase in the incidence of adverse events may occur. A starting dose of 25 mg of another formulation should be considered in the following patient groups since neither DYNAFIL 50 mg nor DYNAFIL 100 mg have score lines to permit halving:

• Age > 65 (40 % increase in AUC)
• Hepatic impairment (e.g. cirrhosis, 80 %)
• Severe renal impairment (creatinine clearance < 30 mL/min, 100 %).

Another formulation should be used for patients requiring a dose of 25 mg.

Patients using potent CYP 3A4 inhibitors

Given the extent of the interaction with patients receiving concomitant therapy with cytochrome P450 3A4 inhibitors (e.g. ritonavir, erythromycin, saquinavir, ketoconazole, itraconazole), DYNAFIL should not be used concomitantly with these medicines (see section 4.3).

Patients receiving alpha-blocker treatment

Patients should be haemodynamically stable on alpha-blocker therapy prior to initiating DYNAFIL treatment in order to minimise the potential of developing postural hypotension (see section 4.4). A starting dose of 25 mg of another formulation should be considered, since neither DYNAFIL 50 mg nor DYNAFIL 100 mg have score lines to permit halving.

DYNAFIL administration is contraindicated in patients who use nitric oxide donors or nitrates in any form as it was shown to potentiate the hypotensive effects of nitrates (see section 4.3).

Paediatric population

DYNAFIL is not indicated for use in children below 18 years of age.

Method of administration

For oral use.

Dynafil is contraindicated in:

• Hypersensitivity to sildenafil or to any of the ingredients of DYNAFIL (see section 6.1)
• Consistent with its known effects on the nitric oxide / cGMP pathway (see section 5.1), DYNAFIL was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated. Doctors should discuss the contraindication of DYNAFIL with concurrent organic nitrates with their patients. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point.
• Patients with severe hepatic impairment (e.g. cirrhosis), severe impairment of renal function (creatine clearance < 30 mL/min) not on haemodialysis or continuous ambulatory peritoneal dialysis.
• Concomitant use of DYNAFIL with potent cytochrome P450 3A4 inhibitors (e.g. erythromycin, ritonavir, saquinavir, ketoconazole and itraconazole) (see section 4.5).
• The co-administration of PDE5 inhibitors, including DYNAFIL, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section 4.5).
• Patients with non-arteritic anterior ischaemic optic neuropathy with loss of vision, regardless of whether this episode was in connection with previous PDE5 inhibitor exposure or not (see section 4.4).

Serious cardiovascular events, including myocardial infarction, sudden cardiac death, ventricular dysrhythmia, cerebrovascular haemorrhage and transient ischaemic attack have been reported post-marketing in temporal association with the use of sildenafil, as found in DYNAFIL, for erectile dysfunction. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil, as found in DYNAFIL, without sexual activity. Others were reported to have occurred hours to days after the use of sildenafil, as found in DYNAFIL, and sexual activity. It is not possible to determine whether these events are related directly to sildenafil, as found in DYNAFIL, to sexual activity, to the patientu2019s underlying cardiovascular disease, to a combination of these factors, or to other factors.

The cardiovascular status of patients should be assessed prior to initiating treatment for erectile dysfunction. DYNAFIL should not be used in men for whom sexual activity is inadvisable. A thorough medical history and physical examination should be undertaken to diagnose erectile dysfunction, determine potential underlying causes, and identify appropriate treatment.

Cardiovascular risk factors:

DYNAFIL has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers. Medical practitioners should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity. Patients with increased susceptibility to vasodilators include those with left ventricular outflow obstruction (e.g. aortic stenosis, hypertrophic obstructive cardiomyopathy), or those with the rare syndrome of multiple system atrophy manifesting as severely impaired autonomic control of blood pressure. DYNAFIL potentiates the hypotensive effect of nitrates (see section 4.3).

Serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular dysrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported post-marketing in temporal association with the use of DYNAFIL. Some of these patients had pre-existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse and a few were reported to occur shortly after the use of DYNAFIL without sexual activity.

Priapism:

Prolonged erections and priapism have been reported with DYNAFIL in post-marketing experience. Patients should seek immediate medical assistance in the event of an erection that persists longer than 4 hours. Priapism (painful erections longer than 6 hours) should be treated immediately, as penile tissue damage and permanent loss of potency could result.

DYNAFIL should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronieu2019s disease) or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).

Concomitant use with alpha-blockers:

Caution is advised when DYNAFIL is co-administered to patients taking an alpha-blocker; administration may lead to symptomatic hypotension (see section 4.5). This is most likely to occur within 4 hours post DYNAFIL dosing (see section 4.5). In order to minimise the potential for developing postural hypotension, patients should be haemodynamically stable on alpha-blocker therapy prior to initiating DYNAFIL treatment. Initiation of DYNAFIL at a dose of 25 mg should be considered (see section 4.2). In addition, doctors should advise patients what to do in the event of postural hypotensive symptoms.

Sensorineural deafness:

A sudden unilateral or bilateral decrease or loss of hearing (sensorineural deafness) with or without associated vestibular symptoms has been reported with the use of PDE5 inhibitors, including DYNAFIL. There is insufficient information regarding the reversibility of the hearing loss and the role of underlying risk factors for hearing loss in individual subjects (see section 4.8). In case of sudden decrease or loss of hearing, patients should be advised to stop taking DYNAFIL and consult a medical practitioner promptly.

Concomitant use with other PDE5 inhibitors or other treatments for erectile dysfunction:

Combinations of DYNAFIL with other treatments for erectile dysfunction is not recommended as the safety and efficacy of such combinations have not been studied.

Effects on vision:

Non-arteritic anterior ischaemic optic neuropathy (NAION) with some loss of vision or irreversible blindness has been reported with the use of selective phosphodiesterase type-5 inhibitors including sildenafil (contained in DYNAFIL). NAION appears to be a class effect of these medicines. Most of these patients had risk factors such as low cup to disc ratio (u201ccrowded discu201d), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidaemia and smoking. Patients should be advised that in the event of any sudden visual defect they should stop taking DYNAFIL and consult their doctor immediately.

Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, medical practitioners should discuss this risk with these patients and whether they could be adversely affected by use of PDE5 inhibitors. PDE5 inhibitors, including DYNAFIL, should be used with caution in these patients and the patientu2019s NAION risk factors should be evaluated when considering prescribing DYNAFIL. NAION appears to be a class effect of these medicines.

A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. There is no safety information on the administration of DYNAFIL to patients with retinitis pigmentosa, therefore, DYNAFIL should be administered with caution to these patients.

There are no controlled clinical data on the safety or efficacy of DYNAFIL in the following patient groups; if prescribed, this should be done with caution.

• Patients who have suffered a myocardial infarction, stroke, or life-threatening dysrhythmia within the last 6 months.
• Patients with resting hypotension (BP 170/110 mmHg).
• Patients with cardiac failure or coronary artery disease causing unstable angina.

Concomitant use with ritonavir:

Co-administration of DYNAFIL with ritonavir is not advised (see section 4.3 and 4.5).

Effect on bleeding:

There are no controlled clinical data on the safety or efficacy of DYNAFIL in patients with bleeding disorders or active peptic ulceration, therefore, DYNAFIL should be administered with caution. DYNAFIL has no effect on bleeding time, including during co-administration with aspirin. Therefore, DYNAFIL should be administered with caution in these patients.

Doctors should counsel patients on the following:

DYNAFIL offers no protection against sexually transmitted diseases. Counselling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered.

The use of DYNAFIL could increase the risk for unwanted pregnancy and suitable contraceptive measures should be taken.

There is potential of prolonged erections greater than 4 hours and priapism in patients taking Dynafil and organic nitrates. The co-administration of Dynafil with regular and/or intermittent use of organic nitrates is contraindicated.

Lactose:

DYNAFIL contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take DYNAFIL.

Women:

DYNAFIL is not indicated for use by women.

Sildenafil may potentiate the hypotensive effect of acute and chronic nitrates. Therefore, the concomitant use of DYNAFIL and nitrates or nitric oxide donors is contraindicated (see section 4.3). Ritonavir increases the plasma concentration of sildenafil significantly and such combinations should not be given (see section 4.4). Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated (see section 4.3).

Effects of other medicines on DYNAFIL

Inhibitors of cytochrome P450 (CYP) isoforms 3A4 (major route of sildenafil) and 2C9 (minor route of sildenafil) which may reduce sildenafil clearance, include the following: cimetidine, erythromycin, itraconazole, ketoconazole, mibefradil, HIV-protease inhibitors such as saquinavir.

Inducers of cytochrome P450 (CYP) isoform 3A4 may increase the metabolism and clearance of sildenafil such as rifampicin. Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has the potential to result in a serious interaction with sildenafil as in DYNAFIL. No effect of concomitant medication on sildenafil pharmacokinetics acting as CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, loop and potassium sparing diuretics, ACE inhibitors, calcium channel blockers, beta-adrenoreceptor antagonists.

Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of DYNAFIL.

Effects of DYNAFIL on other medicines

Concomitant use of DYNAFIL and other antihypertensive medicines may potentiate the antihypertensive effect of these medicines. A mean additional reduction in supine blood pressure (systolic, 8 mmHg; diastolic, 7 mmHg) was observed in concomitant use of sildenafil and amlodipine (see sections 4.2 and 4.4). Concomitant administration of DYNAFIL to patients taking alpha-blocker therapy may lead to symptomatic hypotension in a few susceptible individuals. This is most likely to occur within 4 hours post sildenafil dosing (see sections 4.2 and 4.4). When sildenafil and doxazosin were administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope. Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest increases in plasma levels of sildenafil. DYNAFIL did not potentiate the increase in bleeding time caused by aspirin. No significant interactions were shown between DYNAFIL and tolbutamide (250 mg) or warfarin (40 mg), both being metabolised by CYP2C9 isoenzyme.

Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with mean maximum blood alcohol levels of 80 mg/dL. In healthy male volunteers, sildenafil at steady state (80 mg t.i.d.) resulted in a 49,8 % increase in bosentan AUC and a 42 % increase in bosentan C max (125 mg b.i.d.). Addition of a single dose of DYNAFIL to sacubitril/valsartan at steady state in patients with hypertension was associated with a significantly greater blood pressure reduction compared to administration of sacubitril/valsartan alone. Therefore, caution should be exercised when DYNAFIL is initiated in patients treated with sacubitril/valsartan.

DYNAFIL is not indicated for use in women. DYNAFIL was not found to be carcinogenic, teratogenic, embryotoxic or fetotoxic in animal studies. Single 100 mg oral doses of sildenafil did not impair sperm motility or morphology.

DYNAFIL may have a minor influence on the ability to drive and use machines. DYNAFIL can lead to dizziness and altered vision. Patients should be advised not to drive or operate hazardous machinery or perform hazardous tasks, until they know how DYNAFIL affects them.

a.) Summary of the safety profile

The most commonly reported adverse reactions in clinical studies among sildenafil treated patients were headache, flushing, dyspepsia, nasal congestion, dizziness, nausea, hot flush, visual disturbance, cyanopsia and blurred vision.

b.) Tabulated summary of adverse effects

System Organ Class

Frequency

Side effects

Infections and infestations

Frequent

Less frequent

Flu syndrome

Respiratory tract infection, herpes simplex, pharyngitis, bronchitis, sinusitis, urinary tract infection, laryngitis

Blood and lymphatic system disorders

Less frequent

Anaemia, leukopenia

Immune system disorders

Less frequent

Frequency unknown

Allergic reaction

Hypersensitivity (including skin reactions)*

Metabolism and nutrition disorders

Less frequent

Thirst, oedema, gout, unstable diabetes, hyperglycaemia, hyperuricaemia, hypoglycaemic reaction, hypernatraemia

Psychiatric disorders

Less frequent

Depression, abnormal dreams

Nervous system disorders

Frequent

Less frequent

Frequency unknown

Insomnia, headache, dizziness, pyrexia

Ataxia, hypertonia, neuralgia, neuropathy, paraesthesia, tremor, vertigo, somnolence, migraine, decreased reflexes, hypoaesthesia

Seizure*, seizure recurrence*

Eye disorders

Frequent

Less frequent

Frequency unknown

Abnormal vision (increased perception of light, blurred vision), chromatopsia (mild and transient, predominantly colour tinge to vision)

Conjunctivitis, photophobia, dry eyes, eye haemorrhage, eye pain, cataract

Ocular redness*, mydriasis*, diplopia*, temporary vision loss/decreased vision*, lacrimation disorders*, photopsia*, ocular hyperaemia*, non-arteritic anterior ischaemic optic neuropathy (NAION)*, retinal vascular occlusion*, retinal haemorrhage*, arteriosclerotic retinopathy*, retinal disorder*, glaucoma*, visual field defect*, visual acuity reduced*, myopia*, asthenopia*, vitreous floaters*, iris disorder*, halo vision*, eye oedema*, eye swelling*, eye disorder*, conjunctival hyperaemia*, eye irritation*, abnormal sensation in eye*, eyelid oedema*, scleral discolouration*

Ear and labyrinth disorders

Less frequent

Tinnitus, deafness, ear pain

Cardiac disorders

Frequent

Less frequent

Frequency unknown

Palpitations

Cerebrovascular haemorrhage, transient ischaemic attack, tachycardia, angina pectoris, unstable angina, AV block, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy, atrial fibrillation

Myocardial infarction*, sudden cardiac death*, ventricular dysrhythmia*

Vascular disorders

Frequent

Less frequent

Vasodilation, flushing, hot flushes

Hypotension, hypertension, syncope, postural hypotension, epistaxis, shock

Respiratory, thoracic and mediastinal disorders

Frequent

Less frequent

Nasal congestion, rhinitis

Respiratory disorders, dyspnoea, asthma, cough increased, sputum increased, throat tightness, nasal oedema, nasal dryness

Gastrointestinal disorders

Frequent

Less frequent

Dyspepsia

Vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, oesophagitis, stomatitis, dry mouth, diarrhoea, nausea, abdominal pain, gingivitis, rectal haemorrhage, gastro-oesophagael reflux disease (GORD)

Hepatobiliary disorders

Frequent

Liver function tests abnormal

Skin and subcutaneous tissue disorders

Frequent

Less frequent

Frequency unknown

Flushing, erythema

Urticaria, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis, photosensitivity reaction, face oedema, erythema

Stevens Johnson Syndrome*, Toxic Epidermal Necrolysis (TEN)*

Musculoskeletal, connective tissue and bone disorders

Less frequent

Arthralgia, myalgia, back pain, tenosynovitis, synovitis, arthritis, tendon rupture, arthrosis, bone pain, myasthenia

Renal and urinary disorders

Less frequent

Cystitis, nocturia, urinary frequency/incontinence, haematuria

Reproductive system and breast disorders

Less frequent

Frequency unknown

Gynaecomastia, abnormal ejaculation, prostatic disorder, genital oedema, penile haemorrhage, haematospermia, anorgasmia

Priapism*

General disorders and administrative site conditions

Less frequent

Asthenia, pain, chest pain, chills, peripheral oedema, feeling hot, thirst, irritability

Injury and poisoning

Less frequent

Accidental injury/fall

* Reported during post-marketing surveillance only

Reporting of suspected adverse reactions

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 requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on the SAHPRA website. An email can be sent directly to the company, [email protected], to ensure safety of the product.

Signs and symptoms:

In studies with healthy volunteers, of single doses up to 800 mg, adverse events were similar to those seen at lower doses but incidence rates were increased. Doses of 200 mg did not result in increased efficacy but the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was increased. Side effects may be exacerbated or exaggerated (see section 4.8).

Management of overdose:

Supportive measures should be adopted as required, in the event of an overdose. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and not eliminated in the urine.