MAKLITIO Film-coated tablet Ref.[115231] Active ingredients: Sildenafil

There is no controlled clinical data on the safety or efficacy of sildenafil as in MAKLITIO in the following 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 hypertension (BP >170/110 mmHg).
• Patients with cardiac failure or coronary artery disease causing unstable angina.
• Patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).
• Patients with severe hepatic impairment (see Section 4.3).

Sildenafil as in MAKLITIO 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 certain underlying conditions could be affected adversely by such vasodilatory effects, for example, patients with a low blood pressure, patients with fluid depletion, severe left ventricular outflow obstruction or autonomic dysfunction (see section 4.3).

It was reported that in post-marketing experience with sildenafil (the active ingredient of MAKLITIO) for male erectile dysfunction, serious cardiovascular events, including myocardial infarction, sudden cardiac death, ventricular dysrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, and hypertension, have been reported. 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 without sexual activity. Others were reported to have occurred hours to days after the use of sildenafil and sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors.

MAKLITIO should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia). Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. In the event of any reaction that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result (see section 4.8).

Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell anaemia. Concomitant administration of sildenafil as in MAKLITIO to patients taking alpha-blocker therapy may lead to symptomatic hypotension in susceptible individuals (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 MAKLITIO treatment. Medical practitioners should advise patients what to do in the event of postural hypotensive symptoms.

Sildenafil as in MAKLITIO has no effect on bleeding time, including during co-administration with aspirin. In vitro studies with human platelets indicate that sildenafil as in MAKLITIO potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide donor). There is no safety information on the administration of sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore, MAKLITIO should be administered with caution to these patients.

It was reported that the incidence of epistaxis was higher in patients with pulmonary arterial hypertension secondary to connective tissue disease (sildenafil 12,9%, placebo 0%) than in primary pulmonary hypertension patients (sildenafil 3,0%, placebo 2,4%) and was higher in sildenafil-treated patients treated with concomitant oral vitamin K antagonist (8,8% versus 1,7% not treated with concomitant vitamin K antagonist).

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease. Since there are no clinical data on administration of sildenafil to patients with pulmonary veno-occlusive disease, administration of MAKLITIO to such patients is not recommended.

Non-arteritic anterior ischaemic optic neuropathy (NAION), a cause of decreased vision or loss of vision, has been reported post-marketing with the use of PDE5 inhibitors, including sildenafil. Most of these patients had risk factors such as low cup to disc ratio (“crowded disk”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidaemia and smoking. It is not possible to determine whether NAION is related directly to the use of PDE5 inhibitors or other factors. Medical practitioners should discuss with patients the increased risk of NAION in individuals who have already experienced NAION.

The patients should be advised to seek immediate medical attention in case of sudden vision loss. The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor products, including sildenafil 25 or 50 mg used for erectile dysfunction, has not been studied in PAH patients and such concomitant use is not recommended (see section 4.5).

Effects of other medicines on sildenafil (the active ingredient of MAKLITIO)

In vitro studies

Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.

In vivo studies

Co-administration of oral sildenafil and intravenous epoprostenol has been evaluated (see sections 4.8 and 5.1).

The efficacy and safety of sildenafil co-administered with other treatments for pulmonary arterial hypertension (eg,ambrisentan, iloprost) has not been studied in controlled clinical trials. Therefore, caution is recommended in case of co-administration.

The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitors has not been studied in pulmonaryarterial hypertension patients (see section 4.4).

It was reported that population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the only factors with a statistically significant impact on sildenafil pharmacokinetics in patients with pulmonary arterial hypertension. The exposure to sildenafil in patients on CYP3A4 substrates and CYP3A4 substrates plus beta-blockers was 43% and 66% higher, respectively, compared to patients not receiving these medicine classes.

Sildenafil exposure was 5-fold higher at a dose of 80 mg three times a day compared to the exposure at a dose of 20 mg three times a day. This concentration range covers the increase in sildenafil exposure observed in specifically designed medicine interaction studies with CYP3A4 inhibitors (except more potent CYP3A4 inhibitors e.g. ketoconazole, itraconazole, ritonavir).

It was reported that in a study of healthy male volunteers co-administration of the endothelin antagonist bosentan, which is a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19, at steady state (125 mg twice a day) with sildenafil at steady state (80 mg three times a day) resulted in a 62,6% decrease of sildenafil AUC and a 55,4% decrease in sildenafil C_max. The combination of both medicines did not lead to clinically significant changes of blood pressure (supine and standing) and was well tolerated in healthy volunteers.

It was reported that cimetidine (800 mg), a non-specific CYP3A4 inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers.

It was reported that when a single 100 mg dose of sildenafil was administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg two times daily for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC) (see Section 4.3).

CYP3A4 inhibitors like clarithromycin and telithromycin are expected to have an effect in between that of ritonavir and CYP3A4 inhibitors like saquinavir or erythromycin, a seven-fold increase in exposure is assumed. In addition, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1 200 mg three times daily) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil C_max and a 210% increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics (see Section 4.2). The most potent CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have still greater effects similar to those of ritonavir. (see Section 4.3).

It was reported that co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg twice daily) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C_max and a 1 000% (11-fold) increase in sildenafil plasma AUC. At 24 hours, the plasma levels of sildenafil were still approximately 200 ng/ml, compared to approximately 5 ng/ml when sildenafil was dosed alone. This is consistent with ritonavir’s marked effects on a broad range of P450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics (see Section 4.2). Based on these pharmacokinetic results co- administration of sildenafil with ritonavir is contraindicated. Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of sildenafil.

Co-administration of oral contraceptives (ethinyloestradiol 30 μg and levonorgestrel 150 μg) did not affect the pharmacokinetics of sildenafil. It was reported that in normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for3 days) on the AUC, C_max, T max elimination rate constant or subsequent half-life of sildenafil or its major circulating metabolite.

Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest increases in plasma levels of sildenafil. No dose adjustment is required but the concomitant use of sildenafil and grapefruit juice is not recommended.

Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has the potential to have serious interaction with sildenafil (see section 4.3). Efficacy of sildenafil should be closely monitored in patients using concomitant potent CYP3A4 inducers, such as carbamazepine, phenytoin, phenobarbital, St John’s wort and rifampicin.

Effects of sildenafil on other medicines

In vitro studies

Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC₅₀ >150 μM).

There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.

In vivo studies

It was reported that no significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9.

Sildenafil had no significant effect on atorvastatin exposure (AUC increased 11%), suggesting that sildenafil does not have a clinically relevant effect on CYP3A4.

No interactions were observed between sildenafil (100 mg single dose) and acenocoumarol. Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).

It was reported that sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with mean maximum blood alcohol levels of 80 mg/dl.

It was reported that in a study of healthy volunteers, sildenafil at steady state (80 mg three times a day) resulted in a 49,8% increase in bosentan AUC and a 42% increase in bosentan C_max (125 mg twice daily).

No interaction was seen when sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients. The mean additive reduction on supine blood pressure (systolic, 8 mmHg; diastolic, 7 mmHg) was of a similar magnitude to that seen when sildenafil was administered alone to healthy volunteers (see Section 5.2).

It was reported that in three specific medicine interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilised on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, and mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively were observed. When sildenafil and doxazosin were administered simultaneously to patients stabilised on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in a few susceptible individuals (see Section 4.4).

Sildenafil was shown to potentiate the hypotensive effect of acute and chronic nitrates. Therefore, use of nitric oxide donors, organic nitrates or organic nitrites in any form, either regularly or intermittently with sildenafil is contraindicated (see Section 4.3).

Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated (see section 4.3).

Sildenafil had no clinically significant impact on the plasma levels of oral contraceptives (ethinyloestradiol 30 μg and levonorgestrel 150 μg).

Women of childbearing potential and contraception in males and females

Due to lack of data on effects of sildenafil in pregnant women, MAKLITIO is not recommended for women of childbearing potential unless also using appropriate contraceptive measures.

Pregnancy

There are no data from the use of sildenafil in pregnant women. Animal studies do not indicate direct or indirect effects with respect to pregnancy and embryonal' foetal development. Studies in animals have shown toxicity to postnatal development.

Due to lack of data, MAKLITIO should not be used in pregnant women.

Breast-feeding

It is not known whether MAKLITIO enters the breast milk. MAKLITIO should not be administered to breastfeeding mothers.

Fertility

Non-clinical data revealed no special hazard for humans based on conventional studies of fertility.

As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be aware how they react to MAKLITIO and exercise caution before driving, operating hazardous machinery or performing hazardous tasks.

The most frequently reported adverse reactions that occurred on sildenafil than on placebo were headache, flushing, dyspepsia, back pain, diarrhoea and limb pain.

Tabulated summary of adverse events:

¹ Other side effects reported with sildenafil use not associated with PAH

The overall frequency of discontinuation in sildenafil-treated patients at the recommended daily dose of 20 mg three times a day was low and the same as placebo.

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 sildenafil.

There is insufficient information regarding the reversibility of the hearing loss and the role of underlying risk factors for hearing loss in individual subjects.

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. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

Not applicable.